Clinical Outcomes of Patients with Newly Diagnosed Myelodysplastic Syndrome with MLL Aberrations

Abstract Introduction Mixed lineage leukemias (MLL) are an extremely aggressive subset of leukemias that are inherently resistant to several therapies. MLL aberrations (deletion KMT2A and MLL rearrangements) are extremely rare in myelodysplastic syndrome (MDS) and little is known regarding their clinical course or outcomes. The aim of the study is to determine the natural course of the disease in our patient population. Methods A retrospective cytogenetic database search of patients presenting to a tertiary cancer center from January 2005 to February 2021 with the diagnosis of MDS and CMML with presence of MLL aberrations was conducted. Deletion KMT2A was defined as deletion of 11q23 on cytogenetic studies. Patients who had received prior therapy with hypomethylating agents (HMAs), cytarabine-based regimens, or intensive chemotherapy were excluded. The International Working Group 2006 criteria was used for response assessment. Progression-free survival (PFS) was calculated from date of diagnosis to date of progression from MDS to AML. Overall survival (OS) was determined from the date of diagnosis to the date of death or last follow-up visit. Results Between January 2005 to February 2021, 3369 patients (pts) with the diagnosis of MDS (n=2761) and CMML (n=608) were identified. Of these, 30 pts had MLL aberrations with 18 pts with MLL rearrangements (MLL r) and 12 pts with deletion 11q23 (del-KMT2A). Baseline characteristics are present in Table 1. Among 18 pts with MLL r MDS, 6 pts did not undergo any therapy at our institution. Of the remaining 12, 9 (75%) pts received HMA based therapy, 1 (8%) patient (pt) proceeded to allogeneic stem cell transplant(allo-HSCT) and 2 (17%) pts received intensive chemotherapy (idarubicin, fludarabine and cytarabine). Of the 9 pts who received HMA therapy, 5 (56%) pts had transformation to AML, 2 (22%) pts achieved CR and underwent allo-HSCT, 1 (11%) pt had persistent disease and 1 (11%) developed concurrent metastatic sarcoma and stopped treatment. Out of the 2 (22%) pts who underwent allo-HSCT, 1 pt received maintenance HMA post-transplant but relapsed with transformation to AML after 9 months, and the other was lost to follow up. 1 (11%) pt who had persistent disease received intensive chemotherapy and went into CR and subsequently underwent double umbilical cord transplant and continues to remain in CR. The 2 (17%) pts who received intensive chemotherapy frontline both went into CR, but one developed concurrent malignancy and stopped treatment. The other pt was transitioned to HMA therapy but relapsed with transformation to AML. The 1 patient who received frontline allo-HSCT relapsed with transformation to AML after 5 months. The overall median follow-up duration was 24 months with a median OS of 10 months (Figure 1) and a median PFS of 3.5 months(Figure 2). 12 pts with del-KMT2A were identified, out of which 2 pts did not receive treatment. Of the remaining 10 pts, 8 (80%) received HMA based therapy and 2 (20%) pts received investigational treatments. Of the 8 pts who received HMA therapy, 1 (12.5%) achieved CR and remains in CR, 4 (50%) pts had no response, 2 (25%) had hematological improvement (HI) but one died of other causes and the other elected to stop treatment, 1 (12.5%) pt had transformation to AML. Of the 4 pts with no response, 2 pts elected to stop treatment, with 1 developing concurrent malignancy. Of the remaining 2 pts, 1 pt was placed on an investigational agent and had progression to AML and the other was placed on lenalidomide and then an investigational agent, but ultimately pursued hospice. Of the 2 pts on investigational agents both had persistent disease and one patient died and the other elected to stop treatment due to concurrent illness. The overall median follow-up duration was 154 months with a median OS of 16 months (Figure 1) and median PFS of 8 months (Figure 2). Clinical course is presented in Table 2. Conclusion Prognosis of patients with MLL alterations and MDS is very poor. MLL r MDS had worse outcomes with rapid transformation to AML compared to del-KMT2A. New therapies are needed for this group of patients. Figure 1 Figure 1. Disclosures Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kantarjian: Novartis: Honoraria, Research Funding; Immunogen: Research Funding; Aptitude Health: Honoraria; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria.

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Consolidation with Vtd Significantly Improves the Complete Remission (CR) Rate Following Vtd Induction and Single Autologous Stem Cell Transplantation (auto) in Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v120.21.3096.3096 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3096-3096

Author(s):

Xavier Leleu ◽

Benjamin Hebraud ◽

Guillemette Fouquet ◽

Murielle Roussel ◽

Denis Caillot ◽

...

Keyword(s):

Board Of Directors ◽

Incidence Rate ◽

Relapse Rate ◽

Research Funding ◽

The Other ◽

Newly Diagnosed ◽

Phase 3 ◽

Advisory Committees ◽

Induction Regimen

Abstract Abstract 3096 Background. Several studies have demonstrated the impact of VTd on response rates and PFS either as induction or consolidation regimen. However there are limitations to these studies, especially that no data is available regarding the role of VTd consolidation in the context of bortezomib-triple based VTd induction regimen followed by a single auto. At completion of therapy, the response rate (ORR, PR and better) was 89%, VGPR+CR rate 74%, CR rate 29%, relapse rate and median PFS was 53% and 26 months (median F-up 32 months) in the VTd arm of the phase 3 IFM2007-02 trial conducted for newly diagnosed MM (Moreau et al, Blood 2012). In this study, only a minority of patients had received a consolidation or maintenance. On the other hand, Cavo et al. (Blood 2012) reported 97.5%, 92%, 61%, 39% 3-year progression and 62% estimated 5-year PFS (F-up 43 months) respectively in the VTd arm. VTd was given as induction before and consolidation after double auto in this upfront GIMEMA phase 3 trial (Cavo et al, Lancet 2010). We aimed to assess the efficacy and safety of VTd as consolidation therapy in the context of VTd as induction regimen followed by a single auto (VTd-auto-VTd regimen). Method. This study has included a first group of 121 newly diagnosed MM from 2009 to 2011 across 9 IFM centers. Patients were to be eligible for auto upfront, aged less than 65 and treated with VTd-auto-VTd regimen. The second cohort included MM treated with VTd-auto without consolidation from the IFM2007-02 trial (n=76). A third cohort comprised MM that received upfront a triplet Vd-based combination induction (VCd, VRd) -auto without consolidation (n = 40). Results. In the whole study, the median age was 56 years, the sex ratio was 1,49, 50% had ISS 2 and 3, 22% had adverse FISH [t(4;14); del17p] (similar in the 3 groups). Overall, the ORR was identical in the 3 cohorts at completion of therapy, 104 (86%), 72 (94%) and 32 (80%) for the cohort 1 to 3, respectively. Nevertheless, the CR rate was significantly greater in patients that received a consolidation (cohort 1), as compared to the cohorts 2 and 3 that did not receive any consolidation, 59 (53%) vs. 26 (34%) and 13 (32.5%), respectively (p=0.0001). Interestingly, the CR rates were identical at the end of the induction in the 3 cohorts, 13%, 15% and 22.5%, respectively. With a median follow-up of 25 months, the incidence rate of relapse was significantly greater in the cohort 2 and 3 versus 1, further demonstrating the importance of the consolidation, 25 (21%), 42 (55%) and 13 (32.5%) patients (p=0.0001), respectively; and 9 (8%), 6 (8%) and 8 (20%) had died in cohorts 1 to 3 (p=0.07). The median (95%CI) PFS was not reached in cohort 1, and was 32 (28;36) months and 30 (26;33) months in cohort 2 and 3, respectively. Importantly, 54.5%, 32% and 32% of patients were free of relapse at 32 months in the 3 cohorts, respectively. Similar data were obtained for TTP. The median (95%CI) OS was not significantly different in cohorts 1 to 3, although not reached for the first 2 cohorts and 38 (33;43) months for the 3rdcohort. The 3-year survival was 84%, 91% and 76%, respectively (p=ns). A longer follow up will certainly demonstrate greater survival end points benefit in favor for consolidation. The safety profile of the cohort that contained a consolidation was superimposable to that of the remaining 2 cohorts without consolidation. The incidence rate of hematological EIs of grade 3 and 4 was 4%, 6% and 8% in the 3 cohorts (p=ns), respectively. The incidence rate of neuropathy grade 1–2 and 3–4 was 5% and 2% in the cohort 1 with consolidation, but only 1% occurred during the consolidation. This data compares favorably to the 3% reported in the cohort 2 (Moreau et al. Blood 2012). We have also observed 9 (9%) thromboembolic events (TE), 8 of venous type and 1 arterial. None of them happened during the consolidation, and again, this incidence rate if superimposable to that reported in the IFM2007-02 vTd cohort. Conclusion. This study showed an impressive increase in CR rate in relation to the consolidation that translated into a lower relapse rate. This study also demonstrated that the VTd regimen, used both as induction and consolidation, in the context of a single auto upfront in MM, significantly contributed to improve clinical outcomes with an acceptable toxicity profile. VTd-auto-VTd compared very favorably to the other upfront protocols, and may become in the near future a standard of care in newly diagnosed patients with Myeloma. Disclosures: Leleu: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Onyx: Honoraria, Speakers Bureau; LeoPharma: Honoraria, Speakers Bureau. Off Label Use: Pomalidomide. Roussel:celgene: Honoraria; janssen: Honoraria. Facon:onyx: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees.

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Preliminary Results from a Phase II Study of the Combination of Azacitidine and Pembrolizumab in Patients with Higher-Risk Myelodysplastic Syndrome

Blood ◽

10.1182/blood-2018-99-115720 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 464-464 ◽

Cited By ~ 3

Author(s):

Kelly S. Chien ◽

Jorge E. Cortes ◽

Gautam Borthakur ◽

Courtney D. DiNardo ◽

Naval G. Daver ◽

...

Keyword(s):

Clinical Trial ◽

Myelodysplastic Syndrome ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

International Prognostic Scoring System ◽

Advisory Committees ◽

Genetics Research ◽

Ongoing Phase

Abstract Background: The survival of patients with myelodysplastic syndrome (MDS) after hypomethylating agent (HMA) failure is poor at about 4 to 6 months. The exposure of CD34 positive cells from patients with MDS to HMA has been shown to result in increased expression of PD-1 and PD-L1, with a sequential increase in the expression of PD-1 and PD-L1 particularly in patients that have failed HMA (Yang H, Leukemia 2014). Pembrolizumab is a humanized monoclonal antibody targeting PD-1, thus blocking its interaction with ligands PD-L1 and PD-L2, that has been FDA-approved for certain solid tumors. Consequently, we designed an ongoing phase II clinical trial to evaluate the safety and clinical activity of the combination of azacitidine and pembrolizumab in patients with higher-risk MDS. Methods: Adult patients with intermediate-1 or higher disease by the International Prognostic Scoring System (IPSS) were eligible for the study. Patients were divided into two cohorts: those who had not received prior therapy and those who had not responded to, progressed on, or relapsed after HMA therapy, with a goal enrollment of 20 patients per cohort. Patients received azacitidine 75 mg/m2 IV or SQ daily for 7 days on a 28-day cycle and pembrolizumab 200 mg IV starting on cycle 1 day 1 and every 3 weeks thereafter independent of azacitidine dosing schedule. The endpoints were overall response rate and safety. Patients were discontinued from the clinical trial if there was disease progression, unacceptable adverse experiences, intercurrent illness preventing further administration of study treatment, confirmed positive serum pregnancy test, noncompliance, loss to follow-up, completion of 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of the study medication (whichever occurred later), lack of efficacy, or any other reason leading to the investigator's decision for withdrawal. Clinical trial information: NCT03094637. Results: At data cut-off (July 2018), 18 patients have been treated with azacitidine and pembrolizumab with a median follow-up time of 16 weeks and 9 patients continuing on treatment in cycles 1-6. Twelve patients were enrolled in the HMA failure cohort and 6 patients in the previously untreated MDS cohort. Of the 12 patients evaluable for response, 7 were in the HMA failure cohort and 5 in the previously untreated MDS cohort. In the HMA failure cohort, 1 patient achieved CR, 1 patient demonstrated hematological improvement with mCR or CRi, and 5 patients progressed. In the previously untreated MDS cohort, 1 patient attained CR, 2 patients exhibited hematological improvement, 1 patient showed progression, and 1 patient died due to treatment-unrelated causes. The most frequently observed mutations in the 5 responding patients were TET2 in 3 patients and ASXL1, DNMT3A, and RUNX1 in 2 patients each. Three of the responders had diploid cytogenetics, 1 had del(10), and 1 had complex karyotype. Treatment was overall well-tolerated. Most common treatment-related adverse events (all grades) were neutropenia (22%); elevated ALT, elevated AST, anemia, and injection site reactions (17%); and constipation, joint pain, anorexia, pneumonitis, and pneumonia (11%). Conclusions: In this ongoing phase II trial, preliminary data suggest that azacitidine and pembrolizumab was relatively safe and may have antitumor activity in patients who failed HMA. Disclosures Cortes: Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. DiNardo:Karyopharm: Honoraria; Medimmune: Honoraria; Agios: Consultancy; Bayer: Honoraria; Celgene: Honoraria; Abbvie: Honoraria. Daver:Sunesis: Research Funding; ARIAD: Research Funding; BMS: Research Funding; Karyopharm: Research Funding; Incyte: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy; Otsuka: Consultancy; Kiromic: Research Funding; Daiichi-Sankyo: Research Funding; Karyopharm: Consultancy; Novartis: Consultancy; Incyte: Research Funding; Alexion: Consultancy; Novartis: Research Funding; ImmunoGen: Consultancy; Pfizer: Research Funding. Jain:Adaptive Biotechnologioes: Research Funding; Pfizer: Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Celgene: Research Funding; BMS: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Incyte: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Pharmacyclics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Cellectis: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding; Verastem: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Dose-Adjusted Intensive Chemotherapy Is Safe and Tolerable in Older Patients with Ph-Negative Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2018-99-115634 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5158-5158

Author(s):

Anne S. Renteria ◽

Sangeetha Venugopal ◽

Bridget Marcellino ◽

Alla Keyzner ◽

Marina Kremyanskaya ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Chemotherapy Regimen ◽

Lymphoblastic Leukemia ◽

Intensive Chemotherapy ◽

Advisory Committees

Abstract Background The outcomes of older adults with acute lymphoblastic leukemia (ALL) remain poor when compared to younger ALL patients [PMID 19897583, 28419558, 22409379, 10653870]. Asparaginase (Asp) induces death of human lymphoblasts, and effective asparagine depletion is associated with improved outcomes in ALL. PEG-Asparaginase (PEG-Asp), which has a longer half-life than Asp, is a key component of the intensive chemotherapeutic regimens utilized for treatment of pediatric and younger adult ALL [PMID 29450465]. Frequently, older patients with Ph-negative ALL are not offered PEG-Asp containing pediatric chemotherapy regimen because of concerns related to tolerability and safety in this population [PMID 28355969]. Methods The Adult Leukemia Program at Mount Sinai Hospital developed an age-based, dose-adjusted, CALGB 10403 based intensive chemotherapy regimen for adults (≥40 years) with a diagnosis of Ph-negative ALL. For patients up to 60 years, prednisone (PRD) dose was reduced from 60 to 40 mg/m2/day from D1 to D28, and PEG-Asp reduced from 2500 to 1000 units/m2 (D4). For patients aged 61 years and above, PRD was further reduced to 25 mg/m2/day, and PEG-Asp to 1000 units/m2 on D4. In CD20+ ALL, rituximab x 8 doses were added to the regimen. CNS-prophylaxis consisted of intrathecal methotrexate at D1, D8 and D29 during induction, and during subsequent courses of chemotherapy based on the CALGB 10403 protocol. A PEG-Asp oriented supportive care plan was developed to prevent and treat Asp-related adverse effects. After the administration of PEG-Asp, Antithrombin III (ATIII) and fibrinogen levels were monitored on the same day, twice a week, for at least two weeks. If ATIII levels were < 70% and/or fibrinogen levels < 120 mg/dL, levels were corrected with the administration of ATIII concentrate and/or cryoprecipitate, respectively. Results Twelve patients with a median age of 58 years (45 - 76) were evaluable, and three patients were ≥ 70 years. Nine patients had B-cell ALL and three T-cell ALL. Three patients had a white blood cell count > 30 x103/µL at diagnosis. An ECOG status ≤ 2 at diagnosis was described in all patients, and all of them had multiple complex cytogenetic and molecular abnormalities. Ten patients had significant co-morbidities at diagnosis, including diabetes, hypertension, previous history of cancer, coronary artery disease, obesity, alcohol related chronic pancreatitis, and chronic diarrhea. Nine out of the twelve patients (75%) attained a bone marrow morphological complete remission (CR) at the end of induction (EOI), three of them with detectable minimal residual disease (MRD) that became undetectable after completing course II. Of the three patients who had ≥5% bone marrow blasts at EOI, one attained a CR with undetectable MRD at the end of course IA and another when switched to blinatumomab, and the third one died of progressive disease. No patient experienced early death. Five patients underwent allogeneic hematopoietic stem cell transplantation (HCT) while in CR (age range 46 to 60 years) and four remain in CR at last follow up (median 489 days, range 181 - 841), and one died of relapsed disease 67 days post-HCT. The other six patients who are receiving chemotherapy are alive and in remission at last follow up (median 272 days, range 52 - 639). The common adverse effects associated with PEG-Asp administration in this older group of patients were asymptomatic hypofibrinogenemia and depleted ATIII levels requiring supplementation (n=8), severe hyperbilirubinemia (n=1), and non-life-threatening venous thrombosis (n=1). Severe allergic reaction, clinical pancreatitis and cognitive impairment were not observed. Conclusion This age-based dose-adjusted PEG-Asp containing regimen was associated with an encouraging CR rate and a tolerable and manageable adverse event profile in this older patient population with significant co-morbidities. Treatment related mortality was 0%. Ten of 12 patients are currently in sustained remission, either with chemotherapy alone or following allogeneic HCT (median follow up 422 days, range 52 to 841 days). Treatment optimization for older patients with ALL utilizing an intensified, age-adjusted PEG-Asp containing induction and consolidation therapy regimen is associated with favorable outcomes and provides an effective bridge to potentially curative therapies such as HCT. Further prospective evaluation is under way. Table. Table. Disclosures Kremyanskaya: Incyte: Research Funding. Mascarenhas:Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Promedior: Research Funding; Janssen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding.

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Prognostic Value of Circulating Bcl-2/Igh Levels before and after Treatment in 415 Patients with Advanced Follicular Lymphoma Receiving First-Line Immuno-Chemotherapy in 2 Prospective StiL Trials - the Effect of Rituximab Maintenance

Blood ◽

10.1182/blood-2018-99-118750 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4149-4149

Author(s):

Guido Kobbe ◽

Sabrina Pechtel ◽

Fabian Zohren ◽

Jürgen Barth ◽

Alexander Christoph Burchardt ◽

...

Keyword(s):

Prognostic Factor ◽

Maintenance Therapy ◽

Follicular Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

The Other ◽

First Line ◽

Advisory Committees ◽

Rituximab Maintenance

Abstract Introduction. The prognosis of patients with follicular lymphoma (FL) has improved during recent years following the introduction of immuno-chemotherapy and Rituximab maintenance. Nevertheless, some patients still relapse early and have a poor prognosis. Several prognostic scoring systems have been developed using clinical, laboratory as well as molecular data, while the early identification of high-risk patients remains a challenge. In this context, the relevance of circulating bcl2/IgH levels for patient stratification is not clear. We could show that high circulating bcl2/IgH levels in the peripheral blood (PB) before therapy were an independent adverse prognostic factor for progression free survival (PFS) in patients receiving R-CHOP or Bendamustine-Rituximab (B-R) in the NHL1 study of the German StiL group (Zohren et al, Blood 2015). Methods. Using a sensitive quantitative PCR method as previously described (Zohren et al, Blood 2015), a total of 2,491 circulating bcl-2/IgH level analyses were performed on PB samples before (n=415) and after (n=305) 6 cycles first-line immuno-chemotherapy and during follow-up (n=1,771). Results of these molecular studies were correlated with clinical outcome. We first present a 10-year update of the 107 bcl2/IgHpositive patients from the StiL-NHL1-trial. Secondly, we report the results from the StiL-NHL7-trial including bcl2/IgH analyses of 308 bcl2/IgHpositive patients who received B-R and Rituximab maintenance. Results. With a median follow-up of 10 years in the 107 bcl2/IgHpositive patients from the StiL-NHL1-trial, high PB bcl-2/IgH levels (bcl-2/IgH to reference gene (tPA) ratio >1) before treatment as compared to low (ratio <1) levels remained a major independent prognostic factor for PFS (median 22 vs 71 months, HR 2.27, 95% CI 1.37-3.75; p=0.001). We also confirm that patients who were still bcl-2/IgHpositive after six cycles of immuno-chemotherapy had significantly inferior PFS (13 vs 79 months, Hazard Ratio (HR) 2.97, 95% CI 1.53-5.78; p=0.001) and overall survival (OS, 128 months vs not reached , HR 3.90, 95% CI 1.39-11.00; p=0.010). In contrast, among the 308 bcl-2/IgHpositive patients of the StiL-NHL7-trial, who all received B-R and Rituximab maintenance, PB bcl-2/IgH levels (ratio >1 vs <1) before therapy were no longer prognostic for PFS (99 months vs not reached, HR 1.06, 95% CI 0.66 - 1.69; p=0.814) or OS. On the other hand, being bcl-2/IgHpositive after 6x B-R remained a poor prognostic factor for PFS (43 months vs not reached, HR 2.44, 95% CI 1.18-5.04; p=0.016 ) and OS (72 months vs not reached, HR 4.03, 95% CI 1.82-8.96; p=0.001) despite Rituximab maintenance. When comparing StiL-NHL1 and StiL-NHL7 patients with respect to bcl-2/IgH levels and the effect of Rituximab maintenance, we found that Rituximab maintenance led to a significantly better PFS. In patients with low (ratio <1) bcl-2/IgH levels before therapy the hazard ratio of 1.7 was modest (71 months vs not reached, HR 1.70, 95% CI 1.16-2.50; p=0.006) in comparison to 3.46 as observed in patients with high (ratio >1) bcl-2/IgH levels (22 vs 99 months, HR 3.46, 95% CI 1.93-6.20; p<0.000). These findings suggest that patients with high bcl-2/IgH levels before therapy have a greater benefit from Rituximab maintenance therapy. There was no difference with regard to OS between StiL-NHL1 and StiL-NHL7 patients who were still bcl-2/IgHpositive after 6 cycles of immuno-chemotherapy implying that these patients may not benefit from Rituximab maintenance. Conclusion. High circulating bcl-2/IgH levels in the PB before first line therapy identify a subgroup of patients with advanced FL who have significantly shorter PFS after standard immuno-chemotherapy. These patients greatly benefit from the addition of Rituximab maintenance, because pre-treatment bcl-2/IgH levels lose their predictive value with Rituximab maintenance therapy. On the other hand, patients who remain bcl-2/IgHpositive after standard immuno-chemotherapy have short PFS and OS despite treatment with Rituximab maintenance and therefore are candidates for experimental treatment approaches. Disclosures Kobbe: Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding. Zohren:Pfizer Inc.: Employment. Buske:Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Research Funding. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Greil:Sandoz: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Schroeder:Celgene: Consultancy, Honoraria, Research Funding. Rummel:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Astellas: Honoraria; Eisai: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Symbio: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Outcomes of Myeloma Patients with t(11;14) Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVD) Induction Therapy

Blood ◽

10.1182/blood-2018-99-119051 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3282-3282 ◽

Cited By ~ 1

Author(s):

Jonathan L Kaufman ◽

Nisha Joseph ◽

Vikas A. Gupta ◽

Charise Gleason ◽

Craig C Hofmeister ◽

...

Keyword(s):

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Data Monitoring Committee ◽

The Other ◽

Control Group ◽

Advisory Committees ◽

Post Induction ◽

Standard Risk

Abstract Background: In the cytogenetic risk-stratification of myeloma, identification of t(11;14) on plasma cells has long been regarded as a standard risk prognostic factor. More recently, there have been reports of inferior PFS and OS relative to the standard risk myeloma patients. These results carry significance in the current day, as an ongoing phase I trial of Bcl-2 inhibitor (venetoclax) reported an ORR of 40% among myeloma patients with t(11;14) leading way for individualized therapeutic approach for myeloma. In this context, we evaluated the clinical outcomes of t(11;14) myeloma patients receiving uniform modern day induction therapies to evaluate the prognostic implication of this translocation. Methods: Of the 1000 consecutive newly diagnosed myeloma patients treated with RVD induction therapy per Richardson et al (Blood 2010) from July 2005 until August 2016, we have FISH probes for t(11;14) tested in 867 patients. Among these patients, we identified 122 patients with t(11;14). Excluding 247 patients that had del 17p, t(4;14), t (14;16) and complex karyotype on metaphase cytogenetics, we have identified 527 patients that formed the control group of standard risk myeloma. Demographic and outcomes data for the patients were collected from our IRB approved myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: Median age of the patients is 61 years (range 16-83). 32% of the patients are above the age of 66. Other patient characteristics include: M/F 56%/44%; W/AA 62%/36%; ISS I/II/III 48%/30%/22%; Isotype IgG/IgA/FLC 60%/18%/19%. Response rates are summarized in table 1. Post induction responses ≥VGPR are lower for t(11;14) compared with non-t(11;14): 49.5% vs 76.3% p<0.001 and similarly best VGPR for t(11;14) vs non-t(11;14): 76.3% vs 91.4% p=0.001. The median progression-free survival for the t(11;14) and non-t(11;14) groups were 51 months (95% confidence interval (CI), 30.628-71.372) and 75 months (95% CI, 57.882-92.118) months, respectively (P<0.001), at a median follow up of 39 months. This difference is more pronounced among patients not receiving maintenance therapy (29 vs 62 months, p=0.001). The median overall survival (OS) for t(11;14), and non-(11;14) groups were not reached at a median follow up of 38 months. Conclusions: Even with the use of modern day induction regimens, patients with t(11;14) have inferior outcomes compared to the other patients standard risk myeloma. The lower rates of ≥VGPR post-induction and the shorter median PFS suggests more novel regimens such as venetoclax should be studied earlier in the course to improve the outcomes of t(11;14) patients on par with the other standard risk myeloma patients. Disclosures Kaufman: Janssen: Consultancy; Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Roche: Consultancy; BMS: Consultancy. Hofmeister:Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Heffner:ADC Therapeutics: Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding. Lonial:Amgen: Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Very Long Term Follow up a Phase II Study of Post-Remission Subcutaneous (SC) Azacitidine (AZA) in Patients with AML Post-MDS or Higher-Risk (HR) MDS

Blood ◽

10.1182/blood-2020-137012 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-2

Author(s):

Amina Cherait ◽

Thorsten Braun ◽

Krimo Bouabdallah ◽

Denis Caillot ◽

Agnès Guerci ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Fatal Case ◽

Phase Iii ◽

Long Term Results ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

Ambulatory Treatment

Background: Results of the phase III QUAZAR trial suggest that post-remission treatment with an oral form (CC-486) of azacitidine (AZA) can prolong CR duration and overall survival(OS) in AML patients reaching at least PR with intensive chemotherapy (IC) (Wei et al, ASH 2019). Maintenance treatment with subcutaneous (SC) AZA was recently shown to improve DFS in elderly AML (Huls et al, Blood 2019, a study that also included 10% MDS). We report very long term results of a study evaluating SC AZA as post-remission treatment in patients with AML post-MDS or high-risk MDS (HR-MDS) who achieved at least PR after IC, a population known to have short responses with IC. Methods: Inclusion criteria were (1) HR-MDS according to IPSS, or AML after a documented phase of MDS(2) who entered CR, CRi or PR after IC with anthracycline and AraC within 28 days of inclusion (3) ECOG <= 2, absence of infection or organ toxicity from IC (4) no identified donor for allo SCT at inclusion. Dosing of SC AZA was 60mg/m2/d for 5 days every 28 days, with adjustments according to tolerance, and until relapse or toxicity. Results: From July 2006 to June 2009, 51 pts (M:31/F:20) were included. The 46 evaluable pts had achieved CR (n=28), CRi (n=11), and PR (n=7) before study entry. Median age was 66y (range 55-78). Diagnosis at IC onset was MDS (n=13) and AML (n=33), IPSS cytogenetics was normal (n= 28), intermediate (n=10), high (n= 6), and failed (n=2). Median time from diagnosis of MDS to IC was 8 months (range 0.5-101). Median number of AZA maintenance cycles was 7.5 (1-76) in CR pts (>23 cycles in 5 of them) and 4.5 (1-24) in CRi or PR pts (> 23 cycles in 1). Two patients were allografted and censored at allo SCT. Median follow-up was 16.5 months As of May 2020 (cut off date of analysis) median DFS and OS from response were 6.9 m and 16.9 m, respectively (figure). In CR patients, median and 18 months OS were 18.9 months and 58%, versus 12.8 months and 50% in CRi-PR patients (p=0.33) All non allografted patients eventually relapsed. 7 had a response duration >18 months (6 CR patients: 22, 23, 25, 36, 40, and 84 months; 1 CRi patient: 24 months) OS from inclusion was >3 years in 7 patients (CR pts: 150, 126,74, 51, 50,40 months; CRi pt:58 months), in addition to the 2 allografted pts who remained alive in CR at 156+ and 159+ months No baseline factor including cytogenetics, diagnosis at IC onset (MDS vs AML), % bone marrow blasts, age or time from MDS diagnosis to treatment, significantly predicted DFS or OS. AZA dosing in CR patients was escalated in 9 pts to 75mg/m2/d due to good tolerance but had to be reduced in 6 pts, due to GI toxicity (n=1) and cytopenias (n=5). During SC AZA maintenance, 2/28 CR pts developed febrile neutropenia, compared to 4/18 pts in CRi or PR (including 1 fatal case). In the 22 AML post MDS pts who reached CR, DFS and OS were similar to those observed in 46 AML post AML pts included in a previous ALFA study where pts in CR after IC received DNR/IDA-AraC post-remission therapy (Gardin, Blood 2007). Conclusion: In the very long term analysis of this trial in AML post MDS and HR-MDS treated with induction intensive chemotherapy, post-remission therapy with SC AZA alone was associated with a median DFS and OS of 6.9 and 16.9 months, respectively, with some prolonged response. Results appeared similar to those we had reported with intensive consolidation chemotherapy, but using an ambulatory treatment with limited myelosuppression. Figure Disclosures Braun: Daiichy-Sankyo: Honoraria; Servier: Research Funding. Bouabdallah:Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria. Ades:Celgene/BMS: Research Funding; novartis: Research Funding; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Fenaux:Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

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Comparison of Overall Responses after Standard Induction with High Dose Daunorubicin Versus Standard Dose Daunorubicin with Gemtuzumab Ozogamicin in Favorable Risk Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-129166 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2636-2636

Author(s):

Chetasi Talati ◽

Ryan J Caddell ◽

Katherine Tobon ◽

Rami S. Komrokji ◽

Andrew T Kuykendall ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Statistical Significance ◽

Gemtuzumab Ozogamicin ◽

High Dose ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

Remission Rates

Background: Patients with favorable risk acute myeloid leukemia (AML) by European LeukemiaNet (ELN) criteria are treated with intensive chemotherapy that yields high remission rates and is often curative. Intensive chemotherapy typically includes cytarabine and anthracycline (7+3) with high-dose daunorubicin (dauno 90mg/m2). When compared to 45mg/m2, dauno 90mg/m2 yields superior survival in younger, favorable risk AML patients. Since the re-approval of gemtuzumab ozogamicin (GO), standard practice now incorporates GO in the 7+3 backbone for favorable risk disease, however, it is typically with dauno 60mg/m2 rather than 90mg/m2. We aim to describe responses after 7+3 (dauno 90mg/m2) and 7+3 (dauno 60mg/m2) plus GO (7+3GO) in favorable risk AML. Methods: We retrospectively annotated 56 favorable risk AML patients (pts) who received upfront intensive chemotherapy at Moffitt Cancer Center between 2013 and 2019. They were divided in two cohorts: Cohort A) 7+3 with dauno 90mg/m2; Cohort B) 7+3 with dauno60mg/m2 plus GO at any time during induction or consolidation. Clinical and molecular data were abstracted for each patient in accordance with Institutional Board Review approved protocol. Overall response rates (ORR) included pts achieving complete remission (CR) with minimal residual disease negativity (CRMRD-), CR, CR with incomplete count recovery (CRi). MRD testing included quantitative Real-Time polymerase chain reaction (qRT-PCR) of t(8;21), inv(16) and nucleophosphin 1 (NPM1) tested at least after 2 cycles of intensive chemotherapy. Fisher's Exact method was used to determine significance for categorical variables. All p-values are two-sided. Results: Fifty-six pts were analyzed, including 41 in cohort A and 15 in cohort B. Pt demographics are noted in Table 1. In cohort B, 40.0% received GO on day 1 only (3mg/m2, capped or uncapped), 33.3% received fractionated dosing (3mg/m2 days 1,4,7) and 33.3% received GO during consolidation only. 39.3% of pts had inv(16), 23.2% had t(8;21)(q21.3q22) and 33.9% had mutated NPM1. In all 56 pts, ORR was 94.6%. ORR was 95.1% in cohort A and 93.3% in cohort B (p=0.79). CR rates were 85.4% in cohort A and 73.3% in cohort B (p=0.3) (Table 2). Rate of CRMRD- at any point was higher in cohort B vs cohort A, but did not reach statistical significance (45.8% vs. 20%, p=0.11). CRMRD- was significantly higher in pts with core binding factor (CBF) leukemia in cohort B vs cohort A (81.8% vs. 18.2%, p=0.008). The improvement in CRMRD- was seen in both inv(16) (A vs. B: 22.2% vs. 77.8%, p=0.049) and t(8;21) (0% vs. 100%, p=0.040). In pts with NPM1 mutations, a trend toward higher CRMRD- rates was noted in cohort B but this did not reach statistical significance (A vs. B: 40.0% vs. 100%, p=0.15). Although the median follow up time in cohort B is significantly shorter (12.3 mos in cohort B vs 38.3 mos in cohort A), no difference was observed in the 1-year EFS (68.4% in cohort A and 87.5% in cohort B (p=0.46)) or OS (83.0% in cohort A and 89.0% in cohort B (p=0.96)). No difference was seen in early mortality (30-day) between the two arms (7.3% and 6.7% in cohorts A and B, respectively (p=0.93)). Conclusions: We demonstrate that incorporation of GO to 7+3 with dauno 60mg/m2 yields comparable remission rates to 7+3 with dauno 90mg/m2. Importantly, GO based regimens produce higher rates of MRD negativity compared to 7+3 with dauno 90mg/m2 in CBF leukemia. Longer follow up is needed in order to accurately assess the impact of GO based regimens on overall survival outcomes and whether GO-induced higher MRD negativity rates will translate into superior survival for patients with favorable-risk cohort when compared to 7+3 with high dose daunorubicin. Disclosures Talati: Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau. Komrokji:celgene: Consultancy; pfizer: Consultancy; DSI: Consultancy; Incyte: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau. Kuykendall:Janssen: Consultancy; Abbvie: Honoraria; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. Padron:Incyte: Research Funding. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Stemline: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy.

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Identification of Prognostic Immunophenotypes at First Diagnosis in Patients with Acute Myeloid Leukemia (AML) By a Standardized Multicolor Flow Cytometry (MFC) Panel Originally Designed to Detect Measurable Residual Disease (MRD) at Follow-up

Blood ◽

10.1182/blood-2020-138683 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 35-35

Author(s):

Maximilian Alexander A Rohnert ◽

Malte von Bonin ◽

Michael Kramer ◽

Philipp Ensel ◽

Nadja Holtschke ◽

...

Keyword(s):

Flow Cytometry ◽

Board Of Directors ◽

Research Funding ◽

Prognostic Value ◽

Statistical Significance ◽

The Other ◽

Advisory Committees ◽

Prognostic Relevance ◽

Aberrant Phenotype

Aims In AML, several risk factors obtained at first diagnosis (FD) have been reported to be associated with shorter RFS and OS. The primary prognostic relevance of multicolour flow cytometry (MFC) has been a matter of debate for years. During follow-up (FU), the prognostic relevance of MRD as detected by MFC is less controversial and MFC is recommended in particular (but not exclusive) for those patients (pts) with no reliable genetic marker. We thought to evaluate the prognostic value at FD of a recently established antigen panel and a corresponding analysis strategy, which had been originally developed for MRD-detection. Methods Based on an 8-colour antibody panel (CD45, CD34, CD117, HLA-DR, CD13, CD33, CD7, CD56), we have developed a hierarchical gating strategy with mainly fixed gates. That allows to detect MRD with a high level of standardization and inter-observer reliability (Röhnert M., et al. 25th EHA 2020). Four distinct categories of aberrations (deficiency of CD13 or CD33, cross-lineage expression of CD7 or CD56) detectable on at least 10% of the myeloid blast population were used to define aberrant phenotypes termed leukemia associated immunophenotypes (LAIP) at FD. These categories were also chosen to define MRD during FU. MRDpos by LAIP was defined as the (re-)occurrence of an aberrant category already detectable at FD, while MRDpos by DfN (different from normal) was defined by the de-novo detection of an aberrant category at FU. The prognostic value of the aberrant phenotypes at FD was examined in a cohort of 528 pts. In 122 pts, we further analysed MRD (LAIP/DfN) after completion of intensive induction chemotherapy (IT). Consolidation therapy consisted of allogeneic hematopoietic stem cell transplantation (n=77) or chemotherapy (n=45). The bone marrow samples were measured centrally and analysed independently by three different investigators. Results The probability to achieve a complete remission (CR) varied between the different aberrant phenotypes (LAIP) at FD. Compared to pts without aberrant phenotype (CR rate=68%, n/N=100/148), pts with CD56only (the sole aberrant category was a cross-lineage expression of CD56=only) had a significantly lower CR rate (46%, n/N=15/33, p=0.019). The other exclusive aberrant categories did not significantly influence CR rates compared to pts without LAIP: CD13only (75%, n/N=53/71, p=0.286), CD33only (64%, n/N=59/97, p=0.28) and CD7only (62%, n/N=31/50, p=0.472). In pts with possibly co-occurring aberrant categories (compound aberrant phenotype=comp), the CR rate was significantly higher in CD13comp compared to all other patients (75% vs. 64%, 107/143 vs. 246/385, p=0.018). The other compound aberrancies did not significantly influence CR rates: CD33comp (63% vs. 68%, 90/143 vs. 263/385, p=0.244), CD7comp (66% vs. 67%, 72/109 vs. 281/419, p=0.842) and CD56comp (68% vs. 66%, 84/123 vs. 269/405, p=0.699). Regarding overall survival (OS), just CD56only retained its statistical significance (HR 2.5, CI 1.4-4.7, p=0.004). CD13comp was associated with favourable outcome but without reaching statistical significance (HR 0.7, CI 0.4-1.0, p=0.059). In the cohort of pts with MRD assessment at the end of IT, 67% were classified as responders (CR n=62, CRi n=19) and 33% as non-responders (PR n=14, refractory n=26) by cytomorphology. By MFC, 71% of these pts were classified as MRDpos (n=51/36 responders/non-responders) and 29% as MRDneg (n=30/4). MRDpos was defined by LAIP only (23%), DfN only (44%) or concordantly by LAIP+DfN (33%). OS of MRDneg pts was significantly longer compared to MRDpos patients (HR 4.3, CI 1.0-18.1, p=0.033). Conclusions Using our analysis approach originally developed for MRD monitoring, MFC could provide additional information for initial risk stratification. The presence of an isolated cross-lineage expression of CD56 (CD56only) was associated with a lower CR rate and significant shorter OS. In contrast, CD13comp (CD13 deficiency ± other aberrant categories) was associated with a higher CR rate and prolonged OS. Furthermore, MRDpos as defined by the combined LAIP/DfN strategy provided significant prognostic information. The presented results are currently refined and validated using genetically defined subcategories. The approach has to be confirmed in an independent cohort of pts. Disclosures Rollig: Amgen, Astellas, BMS, Daiichi Sankyo, Janssen, Roche: Consultancy; Abbvie, Novartis, Pfizer: Consultancy, Research Funding. Buecklein:Pfizer: Consultancy; Novartis: Research Funding; Celgene: Research Funding; Amgen: Consultancy; Gilead: Consultancy, Research Funding. Subklewe:Novartis: Consultancy, Research Funding; Janssen: Consultancy; Roche AG: Consultancy, Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Morphosys: Research Funding; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Research Funding. Krause:Pfizer: Honoraria; MSD: Honoraria; Takeda: Honoraria; Gilead: Other: Travel Support; Celgene: Other: Travel Support; Siemens: Research Funding. Schlenk:Roche: Research Funding; AstraZeneca: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; PharmaMar: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Novartis: Speakers Bureau.

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Ramp-up Treatment Strategy in Philadelphia Positive Acute Lymphoblastic Leukemia Is Associated with Deep Molecular Remissions and Favorable Outcomes

Blood ◽

10.1182/blood-2019-128770 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5120-5120

Author(s):

Nabiel A. Mir ◽

Charles Bodine ◽

Denise Peker ◽

Kimo Bachiashvili ◽

Pankit Vachhani ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Fish Analysis ◽

Intensive Chemotherapy ◽

Advisory Committees

Introduction: The advent of Tyrosine Kinase Inhibitors (TKI) changed the treatment paradigm of Philadelphia chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL). Different treatment strategies exist including combinations of TKI with steroids or with intensive multi-agent chemotherapy regimens. We present here our institutional experience of a "ramp-up" strategy using dasatinib with steroids as induction followed by the combination of dasatinib plus the intensive chemotherapy schema of HyperCVAD alternating with HD MTX/cytarabine. Methods: We performed a retrospective review of the electronic medical records of adult patients (pts) treated in our institution for Ph+ ALL. We collected and analyzed data for pts with Ph+ ALL treated with dasatinib and steroids followed by dasatinib plus HyperCVAD alternating with HD-MTX/cytarabine. Results: We identified 25 pts that were treated with the ramp-up treatment approach between 2014-2019. The median age at diagnosis was 45 years old (range 21-65 years old). Fifty-two percent were women and 60% white. Diagnosis of Ph+ ALL was based on FISH analysis with karyotype being positive for the Ph+ chromosomal abnormality in 64% pts; 8% of pts had cryptic translocation and rest not available ( N/A). Sixty percent of pts had p190 Bcr/Abl transcript, 16% had p210 and 8% N/A (including 2 pts that Bcr/Abl transcript was undetectable despite morphological disease). The CD20 by multicolor flow cytometry (MFC) was positive in 16%, heterogenous in 20%, and low/negative in the rest (64%). Eighty-four percent of pts had a WBC less than 50K/cmm at diagnosis; median WBC was 17K/cmm (range 0.8 -131.4 K/cmm). All pts except one received induction with initial dose of 140 mg of dasatinib daily; 84% received prednisone and rest received dexamethasone followed by prednisone. For those pts on dasatinib 140 mg daily, only 2 required adjustment/brief interruption during induction. Eighty-four percent of pts achieved morphological CR, 8% CRp, and 8% had residual ALL post induction with dasatinib and steroids. Of the 23 pts achieving CR/CRp, 34% had minimal residual disease (MRD) by MFC, 26% by FISH analysis and 86% by PCR for Bcr/Abl transcript (21 evaluable pts). Median time from initiation of induction to response bone marrow assessment was 26 days (range 14 - 40 days;75% percentile 28 days). All 25 pts proceeded with HyperCVAD alternating with HD MTX/cytarabine, and the dose of dasatinib used was 70 mg daily (aside from 1 patient who received 100 mg daily). Median time from induction to initiation of HyperCVAD was 34 days (range 17-68 days). The median number of courses (HyperCVAD or HD MTX/cytarabine) for the 25 pts was 3. The 13 pts that ultimately went to transplant in CR1 had also a median of 3 courses. Sixty percent of pts ultimately underwent allo-HSCT. Median time to allo-HSCT from initiation of HyperCVAD was 106 days (range 66-294; 75% percentile 163 days). Overall, all pts achieved CR/CRp with 68% of pts (from the 22 evaluable for molecular remission) attaining also undetectable Bcr/Abl PCR (complete molecular response) as a best response. All pts with post-induction residual disease achieved CR with the dasatinib/intensive chemotherapy combination. Twenty percent of pts had morphological relapse; two pts were treated for non-morphological relapse. Median time to morphological relapse was 148 days from induction (range 106-796 days). The median follow-up was 20.4 months (range 1.5 -58.4; 75% percentile 36.8 months). At last follow up 72% of pts were alive; median OS (not censored for allo-HSCT) was not reached (figure 1). There were no deaths in the first 60 days. Conclusion: Induction therapy with dasatinib and steroids was overall well tolerated and was associated with a very favorable CR/CRp rate, with only a minority of pts requiring treatment adjustment. Subsequent consolidation with dasatinib and HyperCVAD alternating with HD-MTX/cytarabine (+/- allo-HSCT) led to deep remissions in 68% of the pts. Sixty percent of pts underwent allo-HSCT and the median OS was not reached and with no deaths in the first 60 days. Hence, induction therapy with dasatinib and steroids followed by dasatinib plus HyperCVAD alternating with HD-MTX/cytarabine can be considered for Philadelphia chromosome-positive ALL pts to achieve deep remissions with low early mortality. Disclosures Vachhani: AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Costa:Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy. Erba:Amgen, Celgene, Daiichi Sankyo, ImmunoGen, Incyte, Jazz Pharmaceuticals, Millennium, Novartis, Ono, Pfizer, Seattle Genetics, Sunesis: Consultancy; Celgene, Incyte, Novartis: Speakers Bureau; Agios, Amgen, Astellas Pharma, Daiichi Sankyo, ImmunoGen, Janssen, Jazz Pharmaceuticals, Juno, Millennium, Seattle Genetics: Research Funding. Papadantonakis:Agios: Consultancy, Honoraria.

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Comparison of Efficacy and Safety Results in 103 Treatment-Naïve Acute Myeloid Leukemia (TN-AML) Patients Not Candidates for Intensive Chemotherapy Using 5-Day and 10-Day Regimens of Guadecitabine (SGI-110), a Novel Hypomethylating Agent (HMA)

Blood ◽

10.1182/blood.v126.23.458.458 ◽

2015 ◽

Vol 126 (23) ◽

pp. 458-458 ◽

Cited By ~ 6

Author(s):

Hagop M. Kantarjian ◽

Gail J. Roboz ◽

Patricia L. Kropf ◽

Karen W.L. Yee ◽

Casey L. O'Connell ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Complete Response ◽

Intensive Chemotherapy ◽

Phase 2 ◽

Efficacy And Safety ◽

Phase 3 ◽

Advisory Committees ◽

Significant Difference

Abstract Introduction: Guadecitabine (SGI-110) is a novel next-generation HMA administered as a small volume subcutaneous (SC) injection which results in extended decitabine exposure. Phase 2 studies have been conducted in TN-AML patients who were not candidates for intensive chemotherapy using two different doses and schedules of guadecitabine. We report here a comparative efficacy and safety analysis of the 5-day and 10-day regimens. Methods: TN-AML patients who were not candidates for intensive chemotherapy based on age (≥ 65 y), poor performance status (PS 2), comorbidities, or poor risk cytogenetics were enrolled in 2 separate treatment cohorts in the Phase 2 study. In the first cohort, patients were randomized (1:1) to either 60 mg/m2/d or 90 mg/m2/d on Days 1-5 (5-day regimen). In the second cohort, patients were treated with 60 mg/m2/d on Days 1-5 and Days 8-12 (10-day regimen) for up to 4 cycles, followed by 60 mg/m2/d Days 1-5 in subsequent cycles. Cycles were scheduled every 28 days for both regimes with dose reductions/delays allowed based on response and tolerability. Patients remained on treatment as long as they continued to benefit with no unacceptable toxicity. The primary endpoint was the composite Complete Response (CRc): Complete Response (CR) + CR with incomplete platelet recovery (CRp) + CR with incomplete neutrophil recovery (CRi) using modified International Working Group (IWG) criteria (Cheson et al, 2003). Secondary endpoints included overall survival (OS), and safety. Results: There was no difference in efficacy or safety between 60 and 90 mg/m2/d on the 5-day regimen (Yee et al, European Hematology Association meeting 2014, S647), so data are reported here for the two doses combined on the 5-day cohort. There were 51 patients treated in the 5-day regimen cohort and 52 treated with the 10-day regimen. There was no statistically significant difference in patient characteristics between the 2 regimens; median age 77.9 vs. 77.3 years ; male 59% vs. 65%; PS 2 or higher 35% vs. 40%; median BM blasts 40.0% vs. 49.5%; poor risk cytogenetics 46% vs. 43% for the 5-day and 10-day cohorts, respectively. Follow up of the 10-day cohort patients was shorter as it started after completion of enrolment of the 5-day cohort. The median follow up was 25.7 and 12.4 months and median number of cycles was 5 (range 1-26) and 3 (range 1-13) for the 5-day and 10-day cohorts, respectively. There was no significant difference in the primary efficacy endpoint, CRc, between the 2 regimens (p=0.43). CRc was achieved in 29/51 patients (57%) on the 5-day regimen (19 CR, 3 CRp, and 7 CRi) and in 25/52 patients (48%) on the 10-day regimen (16 CR, 5 CRp, and 4 CRi). Median OS was 10.5 and 8.7 months for the 5-day and 10-day cohorts, respectively (p=0.89). The 30, 60, and 90-day all-cause mortality rates were not statistically significant between the two cohorts: 5.9%, 15.7%, and 21.6% on the 5-day regimen and 1.9%, 17.3%, and 28.8% on the 10-day regimen. The most common Grade ≥3 AEs regardless of relationship to guadecitabine were: febrile neutropenia 59% vs. 60%, thrombocytopenia 47% vs. 38%, neutropenia 39% vs. 33%, anemia 27% vs. 19%, pneumonia 24% vs. 27%; and sepsis 12% vs. 19%, for the 5-day and 10-day cohorts respectively, none of which was statistically significant. Fifteen patients remain on treatment (5 from the 5-day cohort and 10 from the 10-day cohort). Conclusions: Guadecitabine is clinically active with a good safety profile in TN-AML patients not candidates for intensive chemotherapy. Unlike in relapsed/refractory AML, where the 10-day regimen of guadecitabine showed a trend toward improved efficacy (Roboz et al, Annals of Oncology 25 Supplement 4, 2014), there was no significant difference in either efficacy or safety between the 5-day and 10-day regimens in newly diagnosed AML patients. Guadecitabine 60 mg/m2/d SC Days 1-5 is currently being investigated in an 800-patient multicenter randomized phase 3 study in TN-AML patients unfit to receive intensive chemotherapy (ASTRAL-1 Phase 3 clinical trial: ClinicalTrials.gov reference NCT02348489). Disclosures Kropf: Teva Pharmaceuticals: Consultancy. O'Connell:Celgene: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Griffiths:Astex: Research Funding; Alexion Pharmaceuticals: Honoraria; Celgene: Honoraria. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Savona:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Rosenblat:Astex Pharmaceuticals, Inc.: Research Funding. Berdeja:Celgene: Research Funding; Onyx: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Array: Research Funding; Curis: Research Funding; Acetylon: Research Funding; MEI: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Takeda: Research Funding. Wilson:Astex Pharmaceuticals, Inc.: Employment. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Issa:Janssen: Consultancy; Astex Pharmaceuticals, Inc.: Consultancy.

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