Combining Imatinib-Following-Nilotinib Treatment in First Line Therapy for Chronic Phase Chronic Myeloid Leukemia. Update from the PhilosoPhi34 Study at 24 Months of Follow-up

Abstract Background Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder which molecular base is represented by the bcr-abl fusion gene, encoding for the constitutionally activated BCR-ABL tirosine-kinase. Three Tirosin-Kinase Inhibitors (TKI) are approved for first line treatment: Imatinib (IM) and the second generation (2G) TKI Nilotinib (NIL) and Dasatinib. 2G TKI are known to provide faster and deeper molecular responses (MR) compared to Imatinib, but serious toxicities may hamper long term treatment with these molecules. Furthermore, 2G TKI were usually employed as second line after IM failure, while the inverse sequence from second to first generation TKI (like an induction-maintenance model) has not been explored yet. We used this schedule in a small group of patients in the PhilosoPhi34 study (EudraCT: 2012-005062-34), a clinical trial designed by the REL (Rete Ematologica Lombarda) cooperative group. This study was composed by three consecutive phases: a Recruitment Phase, a Core Phase (CP) in which patients received NIL 300 mg BID for 12 month (mos), and an Observational Phase (OP), restricted for patients who obtained at least complete cytogenetic response at the end of the CP. During OP, treatment choice was up to the physician and any TKI approved for first line treatment could be used, including IM. In 2017 we presented preliminary data showing that a 12-mos-NIL treatment followed by IM appears as a safe and effective choice for first line therapy in chronic phase CML. Fluctuations in BCR/ABL ratio were similar between IM and NIL treated pts, and the probability of loss of MR4 or MR3 was the same in the two groups; furthermore, despite fluctuations, MR was maintained or improved over time in IM subgroup. Our purpose is to verify these data after 24 mos follow up (FU) at the end of OP. Methods We analyze PhilosoPhi34 database; MR is reported at 3, 6 and 12 mos during the CP and every 6 mos during the OP. The last pt completed the 24 mos of OP in June 2018. Database is still open, evaluations ongoing, and some data can be missing yet: our preliminary observations concern pts with available data of 24 mos OP. Results Seventy-nine pts started the OP. Fourteen pts switched to IM during the OP (Table 1) due to high cardiovascular risk or grade 1-2 chronic AEs . Only 11 pts started IM since the beginning of OP, and we consider these pts in our analysis. Sokal score was high in 2 pts (18%), intermediate in 5 (45.5%), low in 4 (36.5%). At the beginning of OP, 6 pts had a MR ≥ 4 (54.5%), 5 had MR3 (45.5%). At 12 mos of the OP, 7 had MR ≥ 4, 3 had MR3 and 1 had lost MR3 with PCR 0.192%IS (1/5, 20%). At 24 mos of the OP, 9 had MR ≥ 4 (81,8%), and 2 had MR3. Notably, none of pts lost MMR; 2/3 pts(66%) improved response from MR 3 to MR 4 and the pt who transiently lost MMR at 12 mos, recovered it at 24. Sixty-four pts maintained 2G TKI: 62 NIL, 2 other TKI (not considered for analysis). Of them, 4 were lost during this phase: 2 within the first year of OP, other 2 within 12 and 24 mos of OP. In the NIL group, Sokal score was high in 10 pts (16.6%), intermediate in 19 (31.6%) and low in 31 (51.6%). At the beginning of OP, 32 pts had MR ≥ 4 (51.6%), 21 had MR3 (33.8%) and 9 less than MR 3 (14.5%). Responses were improved over time: at 12 mos, 36 pts had MR ≥ 4 (60%), 20 had MR3 (33%) and 4 less than MR3 (6%). At 24 mos 46 pts had MR ≥ 4 (78%), 8 MR3 (13.5%) and 4 less than MR3 (8,5%), Among them, 1 pt experienced disease progression due to a mutation. In particular, during the second year of OP, 11 pts improved response from MR3 to MR ≥ 4(11/20, 55%). Discussion Our data show progressive MR improvement in both IM and NIL group. In particular, risk of loss of MMR is not increased in IM group. More data, more balanced groups and a longer FU are necessary to further confirmations, but after three years of FU, we consider this combination of NIL-followed-by-IM a possible strategy for first line treatment in chronic phase CML, in particular for pts with cardiovascular risk factors. Disclosures Rossi: Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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A Multicenter, Prospective Study for Pediatric Chronic Myeloid Leukemia in Chronic Phase: The JPLSG CML-08 Study

Blood ◽

10.1182/blood-2021-154335 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3605-3605

Author(s):

Hiroyuki Shimada ◽

Akihiro Watanabe ◽

Masaki Ito ◽

Chikako Tono ◽

Haruko Shima ◽

...

Keyword(s):

Children And Adolescents ◽

Myeloid Leukemia ◽

Second Generation ◽

Chronic Phase ◽

Line Treatment ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

First Line Treatment

Abstract Background: Tyrosine kinase inhibitor (TKI) has been used in pediatric chronic myeloid leukemia (CML) for more than 10 years, but only a few prospective clinical studies have been conducted in pediatric patients with CML due to their rarity. We conducted the JPLSG CML-08 study to determine the efficacy and tolerability of TKIs in children and adolescents with newly diagnosed CML in chronic phase (CML-CP). Methods: The JPLSG CML-08 study was a prospective multicenter observational study (UMIN000002581). Patients under 18 years of age with untreated BCR-ABL1-positive CML-CP were eligible and treated according to the modified ELN-2009 recommendation, and the efficacy and safety of TKIs were evaluated. Results: From October 2009 until September 2014, 79 patients were enrolled in 46 hospitals in Japan. A total of 78 patients (49 males and 29 females) were eligible for inclusion. Median age at diagnosis was 11 years (range, 1-17). Median observational period for survivors was 82 months (range, 48-118). Median WBC, Hb and platelet counts were 275x10 9/L (range, 8-765), 9.6g/dL (range, 5.8-14.6) and 560x10 9/L (range, 110-2875), respectively. Splenomegaly was found in 76%. High risk of Sokal, Hasford, EUTOS, and ELTS scores were observed in 21, 13, 27, and 9%, respectively. Clonal chromosome abnormalities in Ph-positive cells occurred in 1 patient at diagnosis. Imatinib, dasatinib, and, nilotinib were used as a first-line treatment in 69 (88%), 7 (9%), and 2 (3%) patients, respectively. The median initial dose of imatinib, dasatinib, and nilotinib was 276, 63, and 262mg/m2, respectively. 5y-PFS and OS was 96.2% (95%CI, 88.6 to 98.7%) and 97.4% (95%CI, 90.1 to 99.4%), respectively. Deaths were observed in 2 patients due to transplant complications. Hematopoietic cell transplantation was conducted in 14 patients (18%). Nine patients (12%) discontinued TKI with the aim of treatment-free remission (TFR), and five of them achieved TFR. In 69 patients with first-line imatinib, complete hematologic response was achieved in 95.7% at 3 months, complete cytogenetic response in 75.4% at 12 months, major molecular response (MMR) in 40.1% at 18 months, and MR4.0 in 52.8% at 60 months; If a transplant was performed, the follow-up period was censored at the date of transplant. Of the 69 patients, 52% changed treatment from imatinib to another TKI or transplant due to poor response, and 20% did due to intolerance. The most common cause of intolerance to imatinib was musculoskeletal events. BCR-ABL1 (IS) <10% at 3 months strongly correlated with higher achievement of MMR, MR4.0, and MR4.5. The EUTOS score was significantly associated with achievement of IS <10% at 3 months. Patients with a first-line second-generation TKI had a higher cumulative incidence of MR4.5 (P = 0.0191) than patients with a first-line imatinib. Second-generation TKI was used as first-line therapy only in patients older than 9 years, but other clinical characteristics, including risk scores, did not differ significantly between the two groups. The incidence of grade 3/4 adverse events (≥ 10%) included neutropenia (47%), anemia (39%), leukopenia (13%), arthralgia (13%), and myalgia (11%) for imatinib, neutropenia (21%), anemia (13%), and thrombocytopenia (11%) for dasatinib, and neutropenia (14%), elevated ALT (14%), hyperbilirubinemia (14%), skin rash (14%), and high CPK (14%) for nilotinib. Gastrointestinal bleeding was an adverse event specific to dasatinib (11% in all grades). Conclusion: This clinical study extends and confirms previous data showing that first-line treatment with imatinib is effective in children and adolescents, with response rates similar to those seen in adults. Although longer follow-up is needed to fully assess the long-term toxic effects, adverse events with imatinib, dasatinib, and nilotinib have been acceptable. As reported in adults, there was an advantage in selecting second-generation TKI over imatinib as first-line therapy to achieve deep molecular remission (DMR). Since discontinuation of TKI after achieving DMR is the preferred strategy, second-generation TKI is expected to become the standard therapy for children and adolescents. Disclosures No relevant conflicts of interest to declare.

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Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

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Predictors of Glucocorticoid Responsiveness in Multicentric Castleman's Disease

Blood ◽

10.1182/blood-2020-136469 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 31-32

Author(s):

Kazutoshi Ebisawa ◽

Arika Nukina Shimura ◽

Akira Honda ◽

Yosuke Masamoto ◽

Fumio Nakahara ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Castleman’S Disease ◽

Line Treatment ◽

Second Line ◽

Castleman's Disease ◽

First Line ◽

Advisory Committees ◽

First Line Treatment

Background: Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disease accompanying various symptoms and multi-organ dysfunctions. Although anti-interleukin-6 monoclonal antibodies, tocilizumab and siltuximab are recommended as a therapeutic option, these treatments require patients to visit hospitals at least once a month for many years, and the drug costs are quite high. In Japan, where tocilizumab is the only biological agent covered by the medical insurance, glucocorticoid monotherapy is still an important treatment option. In fact, a part of MCD patients initially treated with glucocorticoids could be successfully controlled without adding or switching to other agents. Considering that emergence of neutralizing anti-drug antibodies which reduced therapeutic efficacy could also be a clinical problem in MCD, there would be a rationale for reserving newer agents for future relapse by using glucocorticoids as first-line treatment for potential responders. Here, we retrospectively analyzed clinical characteristics of MCD patients treated in our institution to explore factors predicting who could be successfully treated with glucocorticoid monotherapy. Methods: We retrospectively reviewed histologically confirmed Castleman's disease patients who visited the Department of Hematology and Oncology of the University of Tokyo Hospital from January 2000 to March 2020. Based on the diagnostic criteria of Castleman Disease Collaborative Network (CDCN), MCD was diagnosed when enlarged lymph nodes were present in more than 2 lymph node stations and laboratory and/or clinical diagnostic criteria were met. Unicentric Castleman's disease (UCD) was diagnosed when only one single lymph node region was involved. MCD patients who were initially treated with prednisolone (PSL) were divided into two groups: patients who continued PSL until the latest follow-up (PSL-only group) and patients who received subsequent treatment (Second-line group). Results: 8 patients with UCD and 27 patients with MCD were included in our analysis. With a median follow-up of 5.2 years, 21 MCD patients underwent first-line treatment (PSL, n=18; tocilizumab, n=3). Compared to patients who did not receive any treatment, patients who underwent treatment had marginally higher levels of CRP (7.15 mg/dl vs 4.17 mg/dl, respectively; p=0.066) and significantly lower levels of hemoglobin (9.5 g/dl vs 12.5 g/dl, respectively; p=0.036). Seven out of 18 patients initially treated with PSL had received subsequent treatments (tocilizumab, n=6; rituximab, n=1). Among the PSL-only group, biochemical responses at the latest follow-up could be assessed for 10 in 11 patients: two in complete response, five in partial response, two in stable disease, and one in progressive disease, based on the response criteria of CDCN. Compared to PSL-only group, patients classified into second-line group had higher levels of CRP (11.88 mg/dl vs 6.24 mg/dl, respectively; p=0.024) and lower hemoglobin levels (6.4 g/dl vs9.4 g/dl, respectively; p=0.033). Patients whose CRP levels were lower than 12 mg/dl before starting PSL had significantly longer time to next treatment (TTNT) (median not reached vs 0.88 years; HR, 0.078 [95%CI: 0.013-0.48], p=0.00044). Similarly, patients whose hemoglobin levels were more than 8 g/dl had marginally longer TTNT (median not reached vs 2.63 years; HR, 0.22 [95%CI: 0.040-1.17], p=0.054). In addition, patients with either Hb < 8 g/dl or CRP ≧12 mg/dl had significantly shorter TTNT (median not reached vs 2.12 years; HR, 0.090 [95%CI: 0.010-0.77], p=0.0074). The median PSL dose at the latest follow-up in PSL-only group was 3 mg per day [interquartile range: 0-5 mg per day], which would be comparably safe considering previous reports indicating that PSL dose of less than 5 mg per day was associated with lower incidence of adverse events. Conclusion: Out data suggest that glucocorticoid monotherapy has a good potential to induce sustained disease control for MCD patients with higher Hb or lower CRP levels. Furthermore, PSL doses could be tapered to safer doses among patients who could continue PSL until the latest follow-up. In contrast, the efficacy of glucocorticoids for MCD patients with lower Hb or higher CRP levels were limited. Such patients would be good candidates for novel agents such as tocilizumab or rituximab. Disclosures Honda: Nippon Shinyaku Co., Ltd.: Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Speakers Bureau. Nakahara:Eisai Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria. Kurokawa:Chugai: Consultancy, Research Funding, Speakers Bureau; Sanwa-Kagaku: Consultancy; Pfizer: Research Funding; Otsuka: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Teijin: Research Funding; Eisai: Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Nippon Shinyaku: Research Funding, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Bioverativ Japan: Consultancy; Shire Plc: Speakers Bureau; Jansen Pharmaceutical: Speakers Bureau; Ono: Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; MSD: Consultancy, Research Funding, Speakers Bureau.

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Efficacy and Safety of Generic Dasatinib As First-Line Treatment in Patients with Chronic Myeloid Leukemia in Chronic Phase: Final Analysis with 2-Year Follow-up

Blood ◽

10.1182/blood-2021-150197 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3616-3616

Author(s):

Jie Jin ◽

Li Meng ◽

Wenjuan Yu ◽

Peng Liu ◽

Xin Du ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Primary Endpoint ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Line Treatment ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

First Line ◽

First Line Treatment

Abstract Purpose: Generic dasatinib, a second-generation tyrosine kinase inhibitor (TKI), was approved as a second-line treatment for chronic myeloid leukemia (CML) patients in chronic phase (CP) in china. We initiated a prospective, multi-center and single-arm clinical trial (NCT04925141) from May 2016 to October 2018 to evaluate efficacy and safety of generic dasatinib as first-line treatment in China. The primary endpoint was achieved, here we reported the 2 years follow-up results to see its long-term clinical benefit in Chinese patients. Methods:The study included the newly diagnosed CML-CP patients who was diagnosed by the presence of Philadelphia (Ph) chromosome and/or presence of BCR-ABL fusion gene. Key inclusion criteria were as follows: 1) Age ≥ 18 years; 2) The CML subjects in chronic phase with the Ph+ definitive diagnosis were within 6 months before the onset of administration of the study drug; 3) The ECOG performance grades of 0-2; 4) Sufficient main organ functions. All newly diagnosed patients were given 100mg/d (initial dose) of the generic dasatinib. The primary endpoint was molecular major response (MMR) calculated based on the BCR-ABL1 ≤ 0.1% at the 12th month. Secondary endpoints were proportion of subjects who achieved and maintained MMR at 3, 6, and 18 months; Cumulative MMR rates at 6, 12, and 24 months were determined. All patients were followed up through the hospital outpatient departments at second, fourth and eighth weeks, and third, sixth, ninth, twelfth, eighteenth, and twenty-fourth months. The follow-up ended on December 6, 2019. The SAS 9.2 software was utilized for all statistical analyses in this study, and the two-sided test was performed to see variances. Results: A total of 59 patients were included in this trail, with median age of 44 (19 - 70), and 7% of the subjects were at high risk based on the Sokal index for the disease prognosis. The primary endpoint MMR rate at the 12th month was 80.8% which had been published. At 12 months, the cumulative response rate (CCyR) was 85.5% (47/55) and the cumulative MMR was 76.4% (42/55). Here we are reporting the 2 years follow ups. At 24 months, the complete hematological response (CHR) was 88.4%, the cumulative MMR rate was 73.7%, the cumulative MR4.0 rate was 63.6%, the cumulative MR4.5 rate was 58.2%, and the cumulative complete molecular response (CMR) rate was 58.2%. The most common adverse events (AEs) was thrombocytopenia (42.4%) in hematology and pleural effusion (20.3%) in non-hematology, only 11.9% and 1.7% of whom were grade III~IV respectively. Conclusion: This was the first report on domestic dasatinib as the first-line treatment for CML-CP patients received a clinical benefit with 24 months in China. Safety was similar with that of the original study data. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Prognostic Comparison Between ISS and R-ISS in Real-Life Setting of Myeloma Patients: An Example of Utilization of Electronic Biobank Database

Blood ◽

10.1182/blood.v128.22.5645.5645 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5645-5645

Author(s):

Samu Kurki ◽

Klaus Tamminen ◽

Tatu Miettinen ◽

Kari Remes

Keyword(s):

Board Of Directors ◽

Real Life ◽

Hazard Ratio ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Kaplan Meier ◽

Real Life Setting ◽

First Line Treatment

Abstract Introduction: Identification of patients with high-risk (HR) multiple myeloma (MM) is important to optimise their treatment. In 2015, revised International Staging System (R-ISS) guidelines were published (Palumbo, 2015) where HR cytogenetics (CG) and elevated serum lactase dehydrogenase (LDH) were added to the traditional ISS staging criteria. Thus, R-ISS stage III includes one of the HR CG abnormalities or elevated LDH, ISS stage I patients have no HR CG and normal LDH; the rest of patients belong to R-ISS stage II. There are limited data on the prevalence of R-ISS groups in comparison to the old ISS grouping and impact on clinical outcomes in the real-life setting. The aim of the present analysis was to use structured longitudinal electronic health records (EHR) provided by the Finnish Auria Biobank to compare the prevalence and survival outcome between patients in ISS and R-ISS groups in a real-life patient cohort of 100 patients treated at Turku University Hospital. Auria Biobank covers roughly 15% of the population of Finland and collects samples with the associated data from all diseases treated at Turku University Hospital based on the Finnish Biobank Act. Methods: Auria Biobank database was analysed retrospectively for all MM-patients diagnosed between 2008-2013 (incident cohort) and whose fluorescence in situ hybridization analysis was performed at the time of diagnosis. Data for age, gender, LDH, creatinine, ISS, R-ISS, CG, time to next treatment and overall survival were collected from Auria Biobank. Classification into ISS groups was done based on data at the time of diagnosis and OS. Classification into R-ISS staging was done according to IMWG (Palumbo, 2015). For HR CG at least one of the following CG abnormalities was required: del(17), t(4:14), or t(14:16). Estimated glomerular filtration rate was calculated by using the CKD-EPI formula. Drug treatments were classified as conventional (e.g. melphalan + prednisolone) or novel (proteasome inhibitors, IMIDs). Descriptive methods and Kaplan-Meier survival analysis were used for comparison of the groups. Results: The median age of the 100 patients was 64 yrs (range: 37 - 80), and 43% were female. At the time of diagnosis, 17% of patients had high risk CG status, 32% had at least moderate kidney failure (estimated glomerular filtration rate <60ml/min) and 26 % had elevated LDH. 41% patients received autologous stem cell transplant and 64% and 14% were treated with novel and conventional treatments in first line, respectively. 26%, 48% and 26% were classified to ISS stage I, II and III groups respectively, and 21%, 63% and 16% to R-ISS stage I, II and III groups, respectively. Criteria to include patients into R-ISS III were HR CG in 62 %, elevated LDH in 69 % and 31 % fulfilled both criteria. Neither ISS- nor R-ISS staging had any influence on first line treatment decisions between novel and conventional treatments. In all patients 2-year OS (from diagnosis) was 82% (median OS not yet reached). The 2-year OS in ISS I, II and III groups was 90%, 88%, and 60% respectively, and in R-ISS I, II and III groups 87%, 85% and 42%, respectively. R-ISS had a statistically significant effect on survival time (log rank P=0.032), with R-ISS III patients having a 3.8-fold risk of death compared to R-ISS I (Fig 1). R-ISS III patients had also shorter (ns) treatment free survival than R-ISS I patients (HR 2.1, log rank P=0.479) (Fig 2). No statistically significant difference was observed between the survival curves stratified by ISS staging groups. Conclusion: The new R-ISS staging system, using additional information including CG-profile and serum LDH, separated in our real-life setting more profoundly patients with poor prognosis than the old ISS staging. Structured EHRs can successfully be used to derive useful clinical and prognostic data from real-life MM patients. Figure 1 Kaplan-Meier curves for overall survival in different R-ISS groups. Time is measured from diagnosis to death or end of follow-up. Log rank P=0.032. R-ISS III vs. R-ISS I hazard ratio 3.8. Figure 1. Kaplan-Meier curves for overall survival in different R-ISS groups. Time is measured from diagnosis to death or end of follow-up. Log rank P=0.032. R-ISS III vs. R-ISS I hazard ratio 3.8. Figure 2 Kaplan-Meier curves for time to next treatment in different R-ISS groups. Time is measured from beginning of first line treatment to beginning of second line treatment or end of follow-up. Log rank P=0.479. R-ISS III vs. R-ISS I hazard ratio 2.1. Figure 2. Kaplan-Meier curves for time to next treatment in different R-ISS groups. Time is measured from beginning of first line treatment to beginning of second line treatment or end of follow-up. Log rank P=0.479. R-ISS III vs. R-ISS I hazard ratio 2.1. Disclosures Tamminen: Aava Healthcare group: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Roche: Employment; Takeda: Employment. Remes:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Sequential Treatments in Chronic Phase Chronic Myeloid Leukemia (CML) Patients without Optimal Response after Frontline Nilotinib or Dasatinib: An Italian CML Campus Study

Blood ◽

10.1182/blood-2020-141077 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 45-46

Author(s):

Gabriele Gugliotta ◽

Mario Annunziata ◽

Isabella Capodanno ◽

Davide Rapezzi ◽

Immacolata Attolico ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Chronic Phase ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Advisory Committees ◽

Optimal Response ◽

First Line Treatment

INTRODUCTION: Frontline therapy with second generation (2G) tyrosine-kinase inhibitors (TKIs) in chronic phase (CP) chronic myeloid leukemia (CML) patients demonstrated higher efficacy as compared to imatinib, with less patients experiencing treatment failure and progression to advanced disease. However, limited information are currently available on the management and outcome of those CML pts not achieving an optimal response to first-line treatment with a 2G-TKI. AIM: To describe the clinical outcome of CP CML patients without an optimal response to a frontline 2G-TKI that switched to alternative TKIs. METHODS: We performed a retrospective analysis in 22 Centers cooperating within the Italian CML Campus Project. Main inclusion criteria were: 1) diagnosis of CP-CML after 2010; 2) first-line treatment with a 2G-TKI; 3) switch to second-line treatment in case of non-optimal response (either following ELN recommendations or as for clinical practice); 4) CML in CP at the time of switching to second-line treatment. The main exclusion criteria were a switch to second-line treatment for intolerance or for low adherence to therapy. RESULTS: The main findings of this analysis are summarized in the table. Seventy-one pts meeting the inclusion/exclusion criteria were identified; the median age of pts at CML diagnosis was 46 (21-80) years. Sokal risk score was low, intermediate, and high in 24 (34%), 30 (42%), and 17 (24%) pts, respectively. First-line treatment was performed with nilotinib in 47 (66%) pts and dasatinib in 24 (34%) pts. According to the ELN 2020 recommendations, 51 (72%) pts fulfilled the criteria for "failure" and 20 (28%) pts those for "warning". BCR-ABL mutations were identified in 12 of 65 (18%) evaluable pts (T315I in 1 pt). Additional chromosomal abnormalities in Ph+ cells were identified in 6 of 54 (11%) evaluable pts. Second-line treatment was started after a median time of 16 (4-72) months, with ponatinib (40 pts, 56%), dasatinib (21 pts, 30%), nilotinib (7 pts, 10%), or bosutinib (3 pts, 4%). Median follow-up from start of second-line treatment was 25 (2-90) months. Best response to second-line treatment was MR2 in 18 (25%) pts and MR3 in 37 (51%) pts. Nineteen (27%) pts (13 for resistance and 6 for intolerance) switched to third-line treatment (ponatinib, 11 pts; nilotinib, 3 pts; dasatinib, 4 pts; imatinib, 1 pt), after a median time of 8 (1-72) months. Mutations were identified in 2 of 17 evaluable pts, and both patients harbored a T315I mutation. MR3 was reached by 9 (47%) of these pts. Lastly, 7 (10%) pts switched (6 for resistance and 1 for intolerance) to fourth-line treatment (asciminib, 4pts; dasatinib, 2 pts, nilotinib, 1 pt). Overall, 44 (62%) patients reached with sequential TKI treatments a MR3 (31/51 pts among "failures"; 13/20 among "warnings"). Allogeneic stem-cell transplantation (SCT) was performed in 7 (9.5%) pts (6 among "failures"), after a median time of 20 (15-60) months from CML diagnosis. Progression to advanced phase occurred in 2 (3%) pts; both pts previously met the ELN2020 "failure" criteria. Estimated 4-y PFS was 92.5%. Death occurred in 3 (4%) pts (1 after progression to blast phase, 2 for cardiovascular adverse events). Estimated 4-y OS was 93.7% CONCLUSION Our findings show that CP-CML patients not achieving an optimal response to frontline 2G-TKI therapy, despite a complex management, still have a favorable prognosis and survival due to the availability of both multiple TKI options and SCT. Figure Disclosures Gugliotta: Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Galimberti:Novartis: Speakers Bureau; Incyte: 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; Bms: Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bocchia:CELGENE: Honoraria; Incyte: Honoraria. Castagnetti:Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Di Raimondo:Amgen, Takeda, Novartis: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; GILEAD, Incyte: Research Funding; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Rosti:Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Incyte: Speakers Bureau. Saglio:Pfizer: Research Funding; Ariad: Research Funding; Roche: Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Breccia:Abbvie: Consultancy; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

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Effectiveness and Cost of Rituximab for CLL in the Province of Manitoba Prior to Its Approval As Part of First Line Treatment

Blood ◽

10.1182/blood.v120.21.4701.4701 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4701-4701

Author(s):

Pamela Skrabek ◽

Rajat Kumar ◽

James B Johnston ◽

Joseph Baptiste ◽

Bernie Lozar ◽

...

Keyword(s):

Board Of Directors ◽

Clinical Outcomes ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

The Third ◽

Treatment Line ◽

Oncology Drug ◽

First Line Treatment

Abstract Abstract 4701 Introduction: In Manitoba (MB), population 1.25 million, utilization of parenteral oncology drugs is captured through a provincial oncology drug program (PODP) database. The MB Oncology Drug Utility and Clinical Outcomes Program (MODUCO) evaluates drug/regimen utilization with correlation to clinical outcomes. Rituximab (R) accounts for a significant proportion of PODP expenditures, as such monitoring effectiveness at the population level is essential. First line treatment of CLL with FR or FCR was approved in MB in 2009. Prior to this, approval for R based regimens required a non-formulary request. This was a MODUCO initiative to determine effectiveness and cost of R based therapy for CLL in MB, prior to formulary approval of R as part of first line treatment. Methods: Using the PODP database all patients in MB with CLL (and SLL) who received any form of R based therapy between January 14, 2003 and December 14, 2007 were identified. Using this cohort, treatment with R based regimens up until March 14, 2011 was analyzed with follow up until August 1, 2012. Treatment with R for transformed lymphoma was excluded. The primary outcome measure of Treatment Free Survival (TFS) was defined as the interval from initiation of R to next treatment or death. Patients were censored if alive without further treatment at the date of last follow up. The following factors were analyzed for impact on TFS: age, gender, treatment line (greater than or equal to 1), R treatment line (greater than or equal to 1), regimen, treatment indication (symptomatic disease, lymphocyte doubling time (DT), autoimmune cytopenias, or stage 3/4 disease) and response (No /Yes). Response was defined as improvement in peripheral blood counts or reduction in lymphadenopathy and/or organomegaly. Exact dose of R received during each treatment was recorded for cost analysis. Results: Between 2003–2007 R based therapy was administered for the first time to 86 patients (57 males) with mean age 65.1 years. Median number of prior treatments was 3 (range 1–9). Second time treatment with R was given to 40 patients (46.5%) while 12 (14%) received R on three or more occasions during the follow up period. Overall response was seen in 72.4%. The median time to next treatment or death (TFS) was 1.28 years (95% CI 1.01–1.64) with 50 deaths. Factors contributing to shorter TFS based on univariate analysis were (a) lack of response (p<0.0001), (b) 2nd or 3rd time R administration (p 0.04 and 0.0002), and (c) use of RCVP or RCHOP (p <0.02) or other regimens (p <0.001) compared to the reference (FR/FCR). Multivariate analysis revealed that treatment initiation due to DT, compared to all other indications, was associated with decreased rate of retreatment or death (HR 0.36, 95% CI 0.17–0.73). As seen in Figure 1, patients receiving R for the third time (or greater) had shorter median TFS (HR 2.54, 95% CI 1.48–4.36). Regimens other than FR, FCR, RCVP, RCHOP and RCD had increased risk of needing alternative treatment or dying (HR 1.82, 95% CI 1.08–3.06). Mean cost of R per regimen was $12,999.91. The total cost of R for this cohort was $1.87 million. Cost of R when used for the third time or greater was $410,698. Conclusion: This population-based retrospective analysis of cost and effectiveness of R, prior to formulary inclusion for CLL, reveals that patients derive maximum benefit with 1st and 2nd administration of R. These patients had refractory or relapsed disease with multiple prior treatments, yet a high proportion responded to treatment confirming the utility of R for salvage therapy. Duration of response is an important consideration in cost-effectiveness, with the MODUCO experience suggesting that effectiveness diminishes with non-standard regimens and greater than 2 previous R containing regimens. Improving patient access to treatments in health care systems that are publically funded means balancing cost with effectiveness in the population. Disclosures: Kumar: Celgene: Membership on an entity's Board of Directors or advisory committees. Johnston:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bourrier:Roche: Grant Funding for Educational Initiatives Other.

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Treatment Patterns and Outcomes Following Initial Relapse in Patients with Relapsed Systemic Immunoglobulin Light Chain Amyloidosis

Blood ◽

10.1182/blood.v128.22.3338.3338 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3338-3338

Author(s):

Nidhi Tandon ◽

Surbhi Sidana ◽

Morie A. Gertz ◽

Angela Dispenzieri ◽

Martha Q. Lacy ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Al Amyloidosis ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Advisory Committees ◽

First Line Therapy ◽

Line Therapy

Abstract Introduction Immunoglobulin light chain amyloidosis (AL Amyloidosis) is a plasma cell disorder characterized by deposition of misfolded insoluble protein fibrils (composed of monoclonal κ or λ light chains) in tissues causing progressive organ dysfunction. Chemotherapy and autologous stem cell transplant (ASCT), when eligible, are standard treatment options but relapses remain inevitable for most patients. However, there is a paucity of literature describing relapsed or refractory patients. We performed a retrospective study to analyze the outcomes upon relapse and the impact of type of therapy and retreatment with the same therapy at relapse. Methods Clinical and laboratory data of 1327 consecutive patients with systemic AL amyloidosis seen at Mayo Clinic within 90 days of their diagnosis, between 2006 and 2015, was collected by chart review and analyzed retrospectively. Of these patients, 219 (16.5%) were lost to follow-up. Among the remaining 1108 patients, 366 patients experienced a documented hematological or organ relapse or progression requiring change of first line or start of second line therapy and form the current study population. Overall survival (OS) was calculated from start of second line treatment or progression mandating therapy until death from any cause or the date of last follow up. The OS was estimated using the Kaplan-Meier method and log rank test was used to estimate the difference in survival curves. Results The median age was 62.8 years (36.1 - 85.3); 63.1% were males; 64.7% / 59.3% / 11.4% had cardiac / renal / hepatic involvement and 24.2% / 32.1% / 23.3% / 20.3% had MS I/II/III/IV. The median estimated follow up for this cohort was 69.4 months (95% CI; 64.4, 76.8) from the start of first line therapy and 45.2 months (95% CI; 36.5, 50.6) from the start of second line therapy or progression requiring treatment. The median time to second line treatment or relapse /progression mandating therapy was 16.2 months (1-93) from the start of first line therapy. At relapse, 14 patients underwent ASCT, 165 were treated with proteasome inhibitor (PI) based therapy, 83 with immunomodulator (IMiD) based therapy, 33 with alkylator based therapy, 15 with a combination of PI and IMiD, 10 with steroids, 8 with other therapies and 38 did not receive treatment. Among the 366 patients, 124 (33.9%) required change or reinstitution of therapy during follow up at the time of analysis. The median time to third line treatment or relapse /progression mandating therapy was 31 months (95% CI; 24, 40.5) from the start of second line treatment. The median overall survival (OS) was 76.4 months (95% CI; 65.2, 83.6) from the start of first line therapy and 38.8 months (95% CI; 29.6, 52.6) from the start of second line therapy. The type of therapy at relapse (ASCT vs PI vs IMiD vs melphalan vs steroids and others) did not alter the time to next therapy (ASCT, 43.1m; PI, 31m; IMiD, 37m; melphalan, 20.8m; steroids and others, 20m; p=0.3) and OS (ASCT, 66.9m; PI, 51.1m; IMiD, 51.3m; melphalan, 37.2m; steroids and others, 80.7m; p=0.9) from the start of the second line treatment; as depicted in Figure 1. Retreatment with a different drug class (as the first line treatment) at relapse significantly reduced the time to next treatment (32.3m vs 22 m; p= 0.01) as compared to same therapy; but did not have any impact on survival (30.8m vs 51.1m; p = 0.5); as presented in Figure 2. Conclusion This study provides novel information about outcomes of patients with systemic AL amyloidosis who relapse or progress after first line therapy which could be useful in planning salvage therapies and designing clinical trials. Retreatment with a different therapy at relapse improves time to next therapy but does not impact OS. Hence, we conclude that the patients can fare well post relapse/ progression and can benefit from various treatment regimens including retreatment with the same agent. Disclosures Dispenzieri: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; pfizer: Research Funding; Alnylam: Research Funding; Celgene: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Kumar:BMS: Consultancy; Kesios: Consultancy; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding.

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Disease Characteristics of AML Patients with Germline DDX41 Variants

Blood ◽

10.1182/blood-2021-154117 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3384-3384

Author(s):

Jennie Vagher ◽

Shobi Venkatachalam ◽

Peng Li ◽

Julie D. Asch ◽

Bryan D. Huber ◽

...

Keyword(s):

Genetic Testing ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Cultured Skin ◽

Myeloid Neoplasms ◽

First Line Treatment

Abstract Introduction: Germline pathogenic variants in DDX41 represent the most common predisposition to myeloid neoplasms accounting for 1-4% of patients (pts). Myeloid neoplasm with germ line DDX41 mutation is included as a separate entity in the revised 2016 World Health Organization classification of myeloid neoplasms and acute leukemia. The risk to develop any myeloid neoplasm in individuals with pathogenic germline DDX41 variants is modest, estimated to be about 20-30%. The recent inclusion of DDX41 on next generation sequencing panel (NGS) for myeloid neoplasms has led to increase in identification of DDX41 variants. Identification of germline DDX41 variants in MDS/AML pts will inform on donor selection and genetic testing of family members who are potential hematopoietic stem cell transplant (HSCT) donors is critical to eliminate the risk for transmission of a donor derived leukemia. Herein, we describe 10 pts with acute myeloid leukemia who were identified to have a DDX41 variantsince January 2020. Methods Among the pts diagnosed with acute myeloid leukemia in Utah between January 2020 and April 2021, 10 pts were identified to have a DDX41 variant on myeloid NGS panel (peripheral blood or bone marrow) performed at the time of diagnosis (9 pts) or through genetic testing performed on cultured skin fibroblasts (1 pt). When possible, pts with met a genetic counselor and germline genetic testing was performed utilizing DNA obtained from cultured skin fibroblasts through GeneDX Laboratory and Prevention Genetics. DDX41 variants are classified (Table 1) as per the ACMG criteria. Results Of the 10 pts with a DDX41 variant on myeloid NGS panel, 9 (90%) were diagnosed with AML. One pt (10%, Pt 9)) was initially diagnosed as AML and subsequently classified as mixed phenotype T/myeloid leukemia on repeat marrow evaluation after failure of initial induction based on blasts co-expressing cytoplasmic CD3 and MPO. The DDX41 variant was classified as pathogenic and variant of uncertain significance (VUS) in 6 (60%) and 4 (40%) pts, respectively. The variant allele frequency (VAF) of DDX41 variants was above 35% in all pts (Table1). Seven pts had germline testing performed from cultured skin fibroblasts, all were found to have germline DDX41 variants. Three pts did not undergo germline genetic testing, but the VAFs were highly suggestive of germline origin. Baseline demographics and the AML disease characteristics are outlined in Table 1. ELN risk category was unknown in 1 pt (10%), favorable in 1 pt (10%), intermediate in 3 pts (30%) and adverse in 5 pts (50%). Karyotype was normal in6 pts (60%), 20 q deletion in one pt and a complex in 2 pts (20%). Other somatic variants identified on the myeloid NGS panel are outlined in Table 1. First line treatment included intensive chemotherapy in 6 pts (60%) and 4 pts (40%) received hypomethylating agent based (HMA) therapy. Seven pts achieved a complete remission (CR), after first line treatment, of whom 5 received intensive chemo and 2 received HMA based treatment. One pt who received HMA therapy failed to achieve CR or CRi (pt 5), achieved CR after receiving intensive chemo for salvage. One pt failed initial induction with idarubicin and cytarabine (7+3 regimen) and achieved CR after reinduction with cycle 1 A of HyperCVAD. 5 pts relapsed after first line treatment (2 after intensive chemo and 3 after HMA based treatment). At the time of this report, 2 pts received allogeneic stem cell transplant (allo-SCT) both from unrelated donors and 3 pts died. Conclusion: In our experience, AML pts with germline DDX41 variant presented after fifth decade similarly to sporadic AML. Most pts had pathogenic variants in DDX41 (per ACMG), though 3 pts were classified as uncertain variants which represent an area of further knowledge. The majority of the pts had a normal karyotype at diagnosis. A second somatic DDX41 variant was observed in 2 pts. ASXL1 mutations were observed in 3 pts. Inclusion of the DDX41 gene in a myeloid NGS panel is necessary to identify this subset of pts and in addition germline testing should also be considered for all MDS/AML pts with age <40. Multicenter registry-based studies are necessary to further characterize and develop a standardized treatment approach for these individuals and the role of allo-SCT. Figure 1 Figure 1. Disclosures Tashi: PharmaEssentia: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board. Shami: JSK Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Bastion Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chimerix: Research Funding; Takeda: Consultancy; Gilead: Consultancy; BMS: Consultancy; Chimerix: Research Funding; Amgen: Research Funding; Aptevo: Research Funding. Kovacsovics: Stemline: Honoraria; Novartis: Research Funding; Amgen Inc.: Research Funding; Janssen Pharmaceuticals: Research Funding; AbbVie: Research Funding; Jazz Pharmaceutials: Honoraria. Maese: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Tantravahi: Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Research Funding; Abbvie Inc.: Research Funding; CTI BioPharma: Research Funding; Novartis: Research Funding; BMS: Research Funding.

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PET/CT Is a Useful Tool For Both Refining The Definition Of Complete Response (CR) In Multiple Myeloma (MM) and Detecting Otherwise Unrevealed Progression During The Follow-Up Of The Disease: A Single Centre Experience On 282 Patients

Blood ◽

10.1182/blood.v122.21.1936.1936 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1936-1936 ◽

Cited By ~ 2

Author(s):

Elena Zamagni ◽

Cristina Nanni ◽

Annalisa Pezzi ◽

Katia Mancuso ◽

Paola Tacchetti ◽

...

Keyword(s):

Multivariate Analysis ◽

Board Of Directors ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Pet Ct ◽

Prognostic Groups ◽

Definition Of ◽

First Line Treatment

Abstract PET/CT is a reliable technique for assessing skeletal involvement in MM and a valuable tool at the onset of the disease for predicting outcomes in those patients who are eligible to subsequently receive autologous stem cell transplantation (ASCT). However, the prognostic role of PET/CT after treatment and/or during the follow up of the disease, as well as in the non ASCT setting, still remains less defined. To address these issues, we retrospectively analyzed 282 symptomatic MM pts, with a median age of 58 yo, (range 22-83), who were diagnosed and treated in a single institution between 2002 and 2012, and were followed for a median of 66 months. Treatment included ASCT in 70%, novel agents in 77% and was bortezomib-based in 37% of the cases. All the pts were studied with PET/CT at baseline, then every 12-18 months during follow-up, and at the time of each subsequent relapse; for 189 of them PET/CT scans at baseline and 3 months after the end of first line treatment were available. Bone marrow involvement was described as negative, diffuse or focal. The number of focal lesions (FLs), their associated standardized uptake value (SUVmax) and presence of extra-medullary disease (EMD) were recorded. Forty two percent of the pts at diagnosis had > 3 FLs and in 50% of them SUVmax was > 4.2; EMD was present in 5% of the cases. On multivariate analysis, these 3 variables adversely affected PFS and OS, and retained prognostic relevance independently of the treatment received (including or not ASCT, bortezomib- or non-bortezomib-based). On multivariate analysis, ISS stage 3, presence of >3 FLs at PET/CT and failure to achieve CR during or after first line treatment were the leading factors independently associated with shorter PFS and OS. These 3 variables enabled the definition of a scoring system, based on the number of risk factors simultaneously present (score 0: none of the 3 adverse factors, 31% of the pts; score 1: only one out of the 3, 37%, score 2+: 2 or 3 factors, whatever of them, 32% ), that predicted for PFS and OS. More specifically, median PFS was 36 months (mos) for pts with score 0, 58 mos for score 1 and 74 mos for score 2+ (P=0.000). OS was also significantly influenced by the number of adverse factors, with a progressive increase in hazard ratios. A similar stratification into 3 prognostic groups was obtained when SUVmax > 4.2 and presence of EMD replaced FLs>3 within the scoring system. After treatment, PET/CT negativity (PET-CR) was observed in 70% of the pts, while conventionally-defined CR was achieved in 53% of them. Attainment of PET-CR favorably influenced PFS and OS, both in uni and multivariate analyses. Notably, 29% of the pts who achieved CR according to conventional criteria still had positive PET/CT scans: their median PFS was 50 mos as compared with 90 mos for those pts who also achieved PET-CR (P= 0.01) (fig. 1). OS was significantly inferior, as well, for pts not achieving PET-CR, with 6-year estimate of 65% in comparison to 90% for PET negative pts (P=0.0035) (fig. 1). On multivariate analysis, PET-CR was an independent factor predicting for prolonged PFS (P= 0.004) and OS (P= 0.02) within the conventionally-defined CR group. Sixty three percent of the pts experienced relapse or progression, after a median of 56 mos from the end of first-line treatment. In 37% of them, progression was only serological, both serological and skeletal in 48%, only skeletal in 15% and in 12% of these latter patients it was exclusively detected by systematic PET/CT during the follow-up (no pain or pathological fractures). A logistic regression analysis of baseline and post treatment features revealed that persistence of SUVmax > 4.2 after the end of first line treatment was independently associated with exclusive PET/CT progression. In conclusion, PET/CT was confirmed as a reliable predictor of outcome in newly diagnosed MM pts, whatever the treatment. PET/CT combined with ISS stage and attainment of CR to first line therapy was able to split pts in different prognostic groups. Importantly, PET/CT contributed to a more careful and deep evaluation of CR, going beyond the conventionally defined level, and should thus be recommended as a complementary tool to define “true” CR. Finally, in pts with a persistent high glucose metabolism after first line treatment, PET/CT can be recommended during the follow-up, in order to point out possible progression, not otherwise identifiable. Disclosures: Zamagni: Celgene: Honoraria; Janssen-Cilag: Honoraria. Cavo:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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