Response Rate, Event-Free Survival (EFS), and Overall Survival (OS) in Newly-Diagnosed Acute Myeloid Leukemia (AML): U.S. Food and Drug Administration (FDA) Trial-Level and Patient-Level Analyses

Abstract Background: Several novel therapeutics are being developed for AML with demonstrable effects on response rates (e.g. complete remission [CR], CR with incomplete hematologic recovery [CRi], CR with incomplete platelet recovery [CRp], overall response rate [ORR = CR+CRi/CRp]), and EFS. Improvement in EFS recently served as the basis of approval of gemtuzumab ozogamicin (GO) for the treatment of newly-diagnosed CD33-positive AML in adults (Jen et al. Clin Cancer Res 2018). The relationship between response rate, EFS, and OS in newly-diagnosed AML has not been conclusively established. Therefore, we conducted trial-level and patient-level meta-analyses of newly-diagnosed AML trials submitted to the FDA. Methods: We searched for trials submitted with Biologics License or New Drug Applications for treatment of newly-diagnosed AML between 2007 and 2017. Criteria for inclusion were randomized, active-controlled, multicenter trials of intensive AML induction and consolidation chemotherapy. The estimated odd ratios (OR - ratio of odds of response in treatment to odds of response in controls) of CR and ORR and hazard ratios (HR - ratio of hazard of treatment versus control) for EFS and OS were calculated for each study. EFS was defined as time from randomization to treatment failure (defined as date of randomization for patients who failed to achieve CR following induction), disease relapse following CR, or death. Associations between treatment effects at the trial-level were evaluated using weighted least square (WLS) regression analyses on the log-scale (weighted by sample size of each randomized comparison). Coefficient of determination (R2) and 95% confidence interval (CI) were calculated to measure the strength of associations. Individual patient data for OS were plotted against EFS to explore their relationship. An exploratory patient-level responder analysis was performed to compare OS between responders and non-responders, regardless of treatment assignment in the pooled dataset. We estimated HRs of OS from Cox proportional hazards models. OS estimates by response were obtained based on the Kaplan-Meier method. Results: We identified 8 trials with a total of 4482 patients and 3 experimental agents (GO, n=5; [daunorubicin and cytarabine] liposome injection, n=2; midostaurin, n=1) for treatment of newly-diagnosed AML. Two trials tested therapy in defined patient populations (FLT3 mutant = 1 and secondary AML = 1). The association between OS HR and CR OR at the trial-level was moderate (R2 = 0.67, 95% CI: 0.16 - 0.94; Figure 1), whereas the association between OS HR and ORR OR was weak (R2 = 0.43, 95% CI: 0.03 - 0.98). For the OS vs. EFS HR analysis, a weaker than expected association was observed (data to be presented at the meeting). Individual patient level data scatter plots suggested that one possible reason for the lack of a strong association between EFS and OS was that early failures and relapses did not always result in worse OS (Figure 2). In the patient-level responder analysis, patients who achieved a CR response had better OS compared with CRi+CRp response and no response (Figure 3). Conclusions: On a trial level, the meta-analysis of randomized, active-controlled trials in newly-diagnosed AML suggests a moderate association between OS and CR rate, but not ORR. A strong association between EFS and OS is not established and may be confounded by improvements in salvage therapy, supportive care, hematopoietic stem cell transplantation, and/or differing censoring across trials. A patient-level responder analysis showed that CR responders have better OS compared with CRi+CRp responders and nonresponders. While our results are limited by the number of trials, they suggest that CR remains the response endpoint associated with greatest long-term benefit and that EFS, while clinically meaningful, is not a surrogate for OS. Disclosures No relevant conflicts of interest to declare.

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Randomized Phase II Study of Two Schedules of Flavopiridol (Alvocidib, F) Given as Timed Sequential Therapy (TST) Wtih Ara-C and Mitoxantrone (FLAM) for Adults with Newly Diagnosed, Poor-Risk Acute Myelogenous Leukemia (AML)

Blood ◽

10.1182/blood.v116.21.186.186 ◽

2010 ◽

Vol 116 (21) ◽

pp. 186-186 ◽

Cited By ~ 1

Author(s):

Judith E. Karp ◽

John M. Pagel ◽

B. Douglas Smith ◽

Jacqueline M Greer ◽

D. Michelle Drye ◽

...

Keyword(s):

Phase Ii ◽

Kinase Inhibitor ◽

Conflicts Of Interest ◽

Disease Free Survival ◽

Sequential Therapy ◽

Myelogenous Leukemia ◽

Newly Diagnosed ◽

Hematopoietic Stem ◽

Cyclin Dependent Kinase Inhibitor ◽

Poor Risk

Abstract Abstract 186 Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML Therapy F is a protein bound, cytotoxic, cyclin dependent kinase inhibitor. A prior Phase II trial of TST with FLAM, with F given by one hour bolus daily × 3 for adults with newly-diagnosed AML with poor-risk features demonstrated that the complete remission (CR) rate was 30/45 (67%) with median overall survival (OS) and disease-free survival (DFS) for CR patients being 12.6 and 13.3 months, respectively. We now compare FLAM using bolus F (50 mg/m2 daily × 3; Arm A) vs. FLAM using F given by pharmacologically-derived “hybrid” schedule (30 mg/m2 bolus over 30 min followed by 40 mg/m2 in a 4 hr infusion daily × 3; Arm B) in 70 newly-diagnosed AML patients (pts) with poor-risk features. Results: Pt demographics are presented below. Age # < 50 Secondary AML Adverse Genetics MDS/MPD t-AML Single Complex Flt3 ARM A (n = 36) 59ü(24–78) 3 19 5 6 13 3 Total 24/36 = 67% Total 22/36 = 61% ARM B (n = 34) 58ü(20–73) 5 16 9 8 10 5 Total 25/34 = 74% Total 23/34 = 68% Grade > 3 tumor lysis occurred in 4/70 (6%) with 1 death (A), 1 transient hemodialysis (A), 1 transient hyperkalemia (B), and 1 discontinuation of therapy (B). Four pts (6%) died from regimen toxicity before day 60 (1 A, 3 B). Median time for ANC >500/uL was Day 33 (range 22–71), and platelets > 50,000/uL Day 30 (21-80) for both arms. CR rate in Arm A is 23/36 (64%) including 16/24 (67%) with prior MDS and 13/19 (68%) with adverse cytogenetics and 3/3 (100%) with FLT3-ITD. CR rate in Arm B is 24/34 (71%) including 16/24 (67%) with prior MDS, 12/18 (67%) with adverse cytogenetics, and 4/5 (80%) with FLT3-ITD. As of 7/1/10, 20/23 Arm A CR pts have received chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HCT) in CR: 15/23 (65%) of these pts remain alive and in continuous CR for up to 14+ months, 2 relapsed 4 months post-HCT, and 2 died (1 FLAM consolidation, 1 HCT). Similarly, 20/24 Arm B CR pts have received chemotherapy and/or HCT in CR: 12/20 (60%) remain alive and in continuous CR for up to 18+ months. Of Arm B pts receiving FLAM consolidation, 1 relapsed at 2 months, 1 died at 8 months of cardiac failure, and 2 died during therapy. Three were unable to receive a second cycle and 1 refused. Overall, 51/70 (73%) of all pts and 40/47 (85%) of CR pts are alive 2+ - 19+ months after FLAM. Conclusions: TST with FLAM induces CR in >60% of newly diagnosed, poor-risk AML pts, including those with prior MDS and adverse genetics. There does not appear to be major difference in toxicity or responses between the two F schedules (bolus vs. “hybrid” bolus-infusion). Thus far, allogeneic HCT has been successfully undertaken in 21/47 (45%) of first CR patients, median age 57 (20-64), with 2 early relapses and 1 death from GVHD. Bolus F may be easier to administer than hybrid F and is therefore recommended for further study in newly diagnosed AML pts. These salutary results of FLAM in poor-risk pts will now be evaluated broadly in adults with AML and compared to traditional cytotoxic chemotherapy induction regimens. Disclosures: No relevant conflicts of interest to declare.

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Influence of Stem Cell Mobilization After Cyclophosphamide, Thalidomide and Dexamethasone (CTD) Regimen in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.1927.1927 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1927-1927

Author(s):

Jae-Sook Ahn ◽

Deok-Hwan Yang ◽

Sung-Hoon Jung ◽

Soo-Young Bae ◽

Yeo-Kyeoung Kim ◽

...

Keyword(s):

Stem Cell ◽

Induction Therapy ◽

Response Rate ◽

Conflicts Of Interest ◽

Median Number ◽

High Response Rate ◽

Cell Yield ◽

Newly Diagnosed ◽

Cd34 Cells ◽

Cell Mobilization

Abstract Abstract 1927 Backgrounds: CTD regimen has been known as an effective induction therapy in patients with newly diagnosed MM. But, there were inconsistent results for the autologous stem cell yield for transplantation. The aim of present study was to identify the influence of CTD therapy on outcome of peripheral blood stem cell (PBSC) collection. Methods: Forty-eight patients received 4 cycles of CTD therapy. Stem cells were mobilized with cyclophosphamide (3.0 g/m2) and G-CSF (10 ƒÝg/kg, daily) or G-CSF alone. Patients failing to collect ≤ 4.0 × 106 CD34+ cells /kg received a second mobilization courses. Results: The median age at diagnosis was 56 years (range, 39–69). Median duration from start of CTD therapy to first collection was 4.6 months (range, 3.3–8.7). Forty-four patients were mobilized with cyclophosphamide following with G-CSF and 4 patients with G-CSF alone. The median day of apheresis was 3 days (range, 2–7). The response rate for CTD regimen at mobilization was 10% (5/48) of CR, 25% (12/48) of VGPR and 63% (30/48) of PR. A median number of harvested CD34+ cells was 8.6 × 106 cells/kg. At the first mobilization, 83% (40/48) of patients had been reached the minimal PBSC collection target of ≥ 2.0 × 106 CD34+ cells/kg and 71% (34/48) of patients achieved the collection ≥ 4.0 × 106 CD34+ cells/kg. At the end of second mobilization, 90%(43/48) of patients had yields of at least ≥ 2.0 × 106 CD34+ cells/kg and 77% (37/48) of patients had yields of ≥ 4.0 × 106 CD34+ cells/kg. During mobilization period, three patients were developed grade 3/4 non-hematologic adverse events. Conclusion: CTD regimen is an effective induction therapy in patients with newly diagnosed MM showing high response rate and acceptable rate of autologuos stem cell yield without any detrimental effect for the following stem cell collection. Disclosures: No relevant conflicts of interest to declare.

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Role of PDGF/PDGFR in Regulation of Thrombopoiesis: A Possible Explanation for Imatinib Mesylate-Induced Thrombocytopenia in the Treatment of CML

Blood ◽

10.1182/blood.v120.21.3348.3348 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3348-3348

Author(s):

Mo Yang ◽

Fanyi Meng ◽

Jie yu Ye ◽

Yue Xu ◽

Bin Xiao ◽

...

Keyword(s):

Bone Marrow ◽

Imatinib Mesylate ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Potential Effect ◽

Mice Model ◽

Hematopoietic Stem ◽

Platelet Recovery ◽

Bone Marrow Histology

Abstract Abstract 3348 Platelet-derived growth factor (PDGF), a platelet alpha-granule molecule, imply their potential effect in the regulation of megakaryocytopoiesis and thrombopoiesis, which also intimates the existence of an autocrine and/or paracrine loop constructed by megakaryocytes/platelets and their granular constituents. Our previous studies demonstrated the presence of functional PDGF receptors (PDGFR) on human megakaryocytes and platelets (Yang et al, Thromb Haemastasis, 1997) and CD34+ cells, and their ability to mediate a mitogenic response. PDGF promoted the ex vivo expansion of human hematopoietic stem (CD34+) and progenitor (CD41+ CD61+) cells. More significantly, PDGF enhanced the engraftment of human CD45+ cells and their myeloid subsets (CD33+, CD14+ cells) in NOD/SCID mice. PDGF stimulated in vitro megakaryocytopoiesis via PDGFR and/or the indirect effect on bone marrow microenvironment to produce TPO and other cytokines. It also showed a direct stimulatory effect of PDGF on c-Fos, GATA-1 and NF-E2 expressions in megakaryocytes. We speculate that these transcription factors might be involved in the signal transduction of PDGF on the regulation of megakaryocytopoiesis. PDGF also enhanced platelet recovery in mice model with radiation-induced thrombocytopenia. Studies showed that PDGF, like thrombopoietin (TPO), significantly promoted platelet recovery and the formation of bone marrow colony-forming unit-megakaryocyte (CFU-MK) in this irradiated-mouse. An increased number of hematopoietic stem/progenitor cells and a reduction of apoptosis were found in the bone marrow histology sections. In the M-07e apoptotic model, PDGF had a similar anti-apoptotic effect as TPO on megakaryocytes. We also demonstrated that PDGF activated the PI3k/Akt signaling pathway, while addition of imatinib mesylate reduced p-Akt expression. Our findings suggested that the PDGF-initiated radioprotective effect is likely to be mediated via PDGF receptors with subsequent activation of the PI3k/Akt pathway. The study provides a possible explanation that blockage of PDGFR may reduce thrombopoiesis and play a role in imatinib mesylate-induced thrombocytopenia in the treatment of CML. Disclosures: No relevant conflicts of interest to declare.

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Family History Of Hematologic Malignancies and Disorders In a Population Based Study Of Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood.v122.21.1541.1541 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1541-1541

Author(s):

Angela R. Smith ◽

Erica D. Warlick ◽

Rachel K. Fonstad ◽

Michelle A. Roesler ◽

Jenny N. Poynter ◽

...

Keyword(s):

Family History ◽

Conflicts Of Interest ◽

Positive Family History ◽

Hematologic Malignancies ◽

Population Based ◽

Newly Diagnosed ◽

Population Based Study ◽

Hematopoietic Stem ◽

Increased Risk ◽

History Of

Abstract Background MDS is a clonal hematopoietic stem cell disorder characterized by dysplastic changes in the bone marrow, ineffective hematopoiesis and an increased risk for developing acute myeloid leukemia (AML). The majority of MDS cases are sporadic, but rare familial cases have been described and are often ascertained through clinic-based referrals. To our knowledge, no population based study of MDS has examined the frequency of family history of hematologic malignancies and disorders in patients, nor associations with disease characteristics and outcomes. Methods Newly diagnosed MDS cases are being identified by rapid case ascertainment by the Minnesota Cancer Surveillance System (MCSS), a population-based cancer registry in Minnesota. Eligibility criteria include all newly diagnosed cases of MDS during the period April 1, 2010-October 31, 2014, between 20-85 years, Minnesota resident, and ability to understand English or Spanish. Proxy interviews are not being conducted. Medical records and biologic samples are obtained and questionnaires are filled out by participants. Centralized pathology and cytogenetics review confirm diagnosis and classify by subtype and risk score including the Revised International Prognostic Scoring System (IPSS-R). Since 2010, information on family history has been obtained through questionnaire responses and/or medical record review on 353 MDS patients. Cases were considered to have a positive family history if they reported a first degree relative with MDS, leukemia, lymphoma or other hematologic condition (multiple myeloma [n=4], Waldenstrom’s macroglobulinemia [n=1] and idiopathic thrombocytopenic purpura [n=1]). Treatment related MDS cases were excluded leaving 330 MDS patients for analysis. Unconditional logistic regression was used to calculate crude odds ratios (ORs) and 95% confidence intervals (CI) overall and by sex. Results A total of 61/330 (18.5%) cases reported a family history of a hematologic condition. The mean age at diagnosis was 71.3 years in those with a family history compared to 72.2 years in those without a family history (p=0.53). There was no difference in the sex distribution between the two groups. Though not statistically significant, the odds of having abnormal cytogenetics or an IPSS-R of High/Very High was lower for those having a positive family history (OR 0.57 [CI 0.25-1.33, p=0.19 and 0.67 [CI 0.24-1.84, p=0.29], respectively). The odds of survival at one year after diagnosis was significantly higher in those with a family history (OR 2.79 [CI 1.04-7.51, p=0.04]) compared to those without (Table). Further stratification by sex revealed that this association was strongest for males (OR=4.23, [CI 0.94-19.0, p=0.06] compared to females (OR=1.84 [CI=0.47-7.19, p=0.38]). Discussion In this population based study of adults with MDS, the prevalence of MDS cases having a positive family history was higher than previous reports. Additionally, cases reporting a family history of hematologic malignancies and disorders appear to experience lower risk disease and have significantly improved overall survival, especially males. It is possible that patients with a family history of hematologic conditions are diagnosed earlier in the course of their disease secondary to increased awareness about blood disorders and/or more active screening within the family. Our analysis is limited by relatively small numbers, but enrollment is ongoing so subsequent analyses with larger numbers of subjects may be more revealing. Additionally, a prospective study to examine these families further, including detailed medical histories and collection of biospecimens (saliva, blood, skin) for genetic analyses is underway in order to identify potential mechanisms and mutations involved in the development of MDS and progression to AML. Disclosures: No relevant conflicts of interest to declare.

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Low Toxicity Profile of the Combination of Bendamustine Plus Rituximab (BR) in Elderly FRAIL Patients with Newly Diagnosed DLBCL

Blood ◽

10.1182/blood.v124.21.4429.4429 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4429-4429

Author(s):

Michele Spina ◽

Stefano Luminari ◽

Flavia Salvi ◽

Francesco Passamonti ◽

Alberto Fabbri ◽

...

Keyword(s):

Elderly Patients ◽

Response Rate ◽

Conflicts Of Interest ◽

Hematological Toxicity ◽

High Risk Population ◽

Toxicity Profile ◽

Newly Diagnosed ◽

Frail Patients ◽

Low Toxicity ◽

Grade 3

Abstract Introduction: R-CHOP is the gold standard for the treatment of elderly patients with DLBCL. However, unfit and frail patients frequently do not qualify for CHOP-based chemotherapy. Alternatives are an urgent medical need. Bendamustine plus rituximab (BR) has been established as a standard treatment of indolent lymphomas and preliminary data have shown a promising activity in DLBCL, both in the relapsing and upfront setting. Methods: Within the Fondazione Italiana Linfomi (FIL), we started a phase II study (R-BENDA frail study, EUDRACT2011-001421-24) in elderly patients (>70 years) with a newly diagnosed DLBCL not suitable for R-CHOP-based chemotherapy. All patients were evaluated according to ADL, IADL and CIRS-G and were considered FRAIL if the following criteria were meet: in patients aged 70-80 ADL<4 or IADL<5 or one grade 3 comorbidity or >8 grade 2 comorbidities; in patients older than 80 years ADL>5 or IADL>6 or 5-8 grade 2 comorbidities. Patients received bendamustine at a dose of 90 mg/m2 daily on days 1 and 2 of each 28-day cycle along with rituximab on day 1 for up to 6 cycles. Results: From February 2012 to February 2014, 49 patients were enrolled in 24 Italian centers. The majority (57%) were male and 57% had stage III-IV with 41% elevated LDH. The median age was 82. Overall, 83% of the planned cycles were delivered without dose reduction or delay; grade 3/4 neutropenia was reported in 25% of cycles followed by anemia 21%, and thrombocytopenia 20%. One case of febrile neutropenia was observed. Grade 3-4 non-hematological toxicity was mild and reported in 6% of cycles including 3 episodes of cardiovascular events and 7 other cases of different toxicities (one creatinine increase, one fatigue, one bleeding, one peripheral neurotoxicity, one hyponatriemia, one hyperglycemia and one liver toxicity). Two deaths during treatment have been observed (cardiac failure and sudden death). At the interim analysis (23 patients) the overall response rate was 56% with a complete response rate of 39%. Conclusions: Combination therapy with BR demonstrates low toxicity profile in this high risk population. The promising results on activity can encourage clinicians to considered BR for the treatment of FRAIL elderly patients with DLBCL not eligible for R-CHOP. Disclosures No relevant conflicts of interest to declare.

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Evidence That T Cells Specific for Non-Hematopoietic Cells Trigger the Development of Acquired Aplastic Anemia

Blood ◽

10.1182/blood.v126.23.1168.1168 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1168-1168

Author(s):

Tatsuya Imi ◽

Hiroyuki Maruyama ◽

Takamasa Katagiri ◽

Yoshitaka Zaimoku ◽

Kana Maruyama ◽

...

Keyword(s):

T Cells ◽

Aplastic Anemia ◽

Progenitor Cells ◽

Response Rate ◽

Conflicts Of Interest ◽

Uniparental Disomy ◽

Target Cells ◽

Principal Mechanism ◽

Hematopoietic Stem ◽

Number Of Patients

Abstract A T-cell attack against hematopoietic stem cells (HSCs) is believed to be the principal mechanism underlying the development of acquired aplastic anemia (AA). The presence of leukocytes that lack HLA class I alleles as a result of the copy number-neutral loss of heterozygosity of the HLA haplotype due to uniparental disomy in the short arm of chromosome 6 (6pLOH) is compelling evidence for the involvement of cytotoxic T lymphocytes (CTLs) in the HSC destruction; this is based on the high response rate to immunosuppressive therapy (IST) in 6pLOH(+) patients (Katagiri, et al. Blood, 2011). However, target cells of the putative CTLs have not yet been characterized because of the small number of patients analyzed via flow cytometry (FCM) in our previous study. FCM can be substituted for SNP arrays by detecting HLA-A allele-lacking leukocytes (HLA-LLs) caused by 6pLOH. To gain insight into the CTL target responsible for the development of AA, we examined a total of 223 patients (213 idiopathic and 10 hepatitis-associated AA; 93 severe and 130 non-severe AA) for the presence of HLA-LLs and determined the lineage combinations of the aberrant leukocyte population. Of the 223 patients, 145 (65.0%) were heterozygous for the HLA-A allele and could be assessed for the presence of HLA-LLs by FCM. Eighteen (25.4%; 10 with severe AA and 8 with non-severe AA) of the 71 pre-treatment patients, and 26 (35.1%; 13 with severe AA and 13 with non-severe AA) of the 74 post-treatment patients were found to be positive for HLA-LLs. The lineage combinations of HLA-LLs in the 44 HLA-LL(+) patients were granulocytes (Gs), monocytes (Ms), B cells (Bs), and T cells (Ts, GMBT) in 13, GMB in 16 and GM in 11 patients. Surprisingly, HLA-LLs were found in Bs alone in three patients, and in one patient, the lineage combination pattern was TB (Figure). The presence of 6pLOH was confirmed via deep sequencing of isolated Bs from one of the three Bs alone patients. These lineage combination patterns were not observed to change for 1-40 months in 22 of 23 patients whose blood samples were available for follow-up analyses. In one patient with the GMB pattern, HLA-LLs decreased from 11.7% before treatment to 0% after 12 months of ATG therapy. The response rate to IST in GMBT patients (3/4, 75%) and in patients with GMB or GM (9/10, 90%) were similarly higher than in patients without HLA-LLs (22/39, 56%) or in patients who were homozygous for the HLA-A allele (23/36, 64%). Two of the three Bs alone patients showed complete responses at the time of sampling three years after ATG therapy and 20 years after CsA therapy, and another patient had a secondary myelodysplastic syndrome two years after response to ATG. The TB alone patient developed AA 20 years earlier, but had not been treated until recently because there was no need for blood transfusions, and is now improving in response to eltrombapag. This study revealed that the targets of putative CTLs in more than half of AA patients are hematopoietic progenitor cells with limited differentiation but long-lasting capacity, and in some patients, they are lymphoid progenitor cells that do not contribute to hematopoiesis. This suggests that CTL attack against non-HSCs including lymphoid precursors could trigger BM failure. Consistent with our previous report, the bystander effects caused by the immune response to non-HSCs such as myelosuppressive cytokines may play a major role in the development of AA. Disclosures No relevant conflicts of interest to declare.

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DIC and Its Association with Acute Leukemia in Pre-Treatment and Post Remission Induction Phase

Blood ◽

10.1182/blood.v126.23.4665.4665 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4665-4665

Author(s):

Arshi Naz ◽

Tasneem Farzana ◽

Mehwish Taj ◽

Tahir Shamsi

Keyword(s):

Acute Leukemia ◽

Conflicts Of Interest ◽

Strong Association ◽

Treatment Phase ◽

Remission Induction ◽

Induction Phase ◽

Newly Diagnosed ◽

Cross Sectional ◽

Pre Treatment ◽

D Dimer

Abstract Background: Hematological malignancy like acute leukemia (AL) is associated with thromboembolic complications.DIC is a worst complication amongst subtypes of AL especially in APML which can be life threatening. Study design: Descriptive & cross-sectional study. Place and duration of study: National Institute of Blood Disease and Bone Marrow Transplantation; May 2011 to March 2012. Patients and methods: 110 (75 males, 45 females)diagnosed cases of acute leukemia [43 cases of AML (27 newly diagnosed, 16 in remission induction), 67 cases of ALL (38 newly diagnosed; 29 in remission induction)]were included & 40 ascontrols.Mean age of patients was 25.3±13.8.Platelet count,PT, APTT, Fibrinogen levels, D-Dimer &FDP was done for scoring of DIC on day 0 and 28. SPSS version 17 was used for data analysis. Results: Platelet counts significantly improved on day 28 in AML and ALL. PT and APTT levels were significantly deranged. Plasma levels of fibrinogen were higher in both types of acute leukemia in pre-treatment phase, further increased at day 28 (<0.01). FDP significantly raised at day 0 reduced at day 28(AML & ALL). Markedly elevated levels of D-dimer in AML and ALL at day 0,but showed significant reduction at day 28(<0.01). DIC score of <5 was found in 15 (55.56%) patients of AML and 16 (100%) of ALL on day 0 and >5 score was recorded in 12(44.44%) patients of AML on day 28. Conclusion: Strong association of DIC was found in AML and ALL at day 0. Non overt DIC did not show any significant association with specific type of acute leukemia and it was equally expressed in both type of acute leukemia at day 0 and 28. Disclosures No relevant conflicts of interest to declare.

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Engraftment Effects of Intra Bone Marrow Compared to Intravenous Transplantation of Allogeneic Hematopoietic Stem Cells Following a Reduced Intensity Conditioning in a DLA-Identical Canine Littermate Model

Blood ◽

10.1182/blood.v124.21.1089.1089 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1089-1089

Author(s):

Juliane Werner ◽

Stephanie Schaefer ◽

Sandra Lange ◽

Christoph Machka ◽

Gudrun Knuebel ◽

...

Keyword(s):

Bone Marrow ◽

Conflicts Of Interest ◽

Control Group ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Platelet Recovery ◽

Time Points ◽

Donor Chimerism ◽

Cell Counts ◽

Reduced Intensity

Abstract Introduction: Successful engraftment following hematopoietic stem cell transplantation (HSCT) depends on factors like immunosuppression, graft composition and number of infused HSC. Whereas the immunosuppression as well as the type and composition of the graft are influenceable low numbers of available HSCs i.e. “weak grafts” remain a clinical challenge. Weak grafts are accompanied by increased graft failure rates and longer cytopenias associated with increased morbidity. Intra bone marrow (IBM) infusion of HSC might be an approach to overcome these problems. Studies in rodents demonstrated faster engraftment with an IBM HSCT approach compared to intravenous (IV) HSCT following myeloablative conditioning. Studies of IBM HSCT following non-myeloablative or reduced intensity conditioning (RIC) are missing. Aims: Exploring the feasibility and efficiency of IBM allogeneic HSCT in comparison to IV HSCT in dog leukocyte antigen (DLA) identical canine littermates using a RIC regimen. Methods: DLA-identical siblings were used as donor/recipient pairs for HSCT. Recipient dogs were conditioned with 4.5 Gy total body irradiation before HSCT (d0) and received 15 mg/kg Cyclosporin A BID as pre- and postgrafting immunosuppression (d-1 to d+35). BM grafts were harvested at d0. In the control group (CON, n=7) unmodified BM was transplanted IV. In the IBM group (n=7) BM harvests were centrifuged and buffy coat of the BM was then transfused simultaneously into the recipient humeri and femura (50 ml, 10 min). 10 dogs are currently evaluable. Chimerism of the peripheral blood mononuclear cells (PBMC) and granulocytes (G) were tested weekly until week 8 and afterwards in larger intervals. Blood cell counts and clinical toxicities such as weight loss were monitored. Results: Infusion of BM directly into the bone was feasible. All animals engrafted. Median number of infused total nucleated cells was 4.0*108/kg (range 2.3-6.0*108/kg, IBM) and 3.3*108/kg (range 1.9-5.0*108/kg, CON, IBM vs CON: p=0.4). Median CD34+ numbers infused were 3.1*106/kg (range:1.2-10.0*106/kg, IBM) and 3.9*106/kg (range: 1.0-7.2*106/kg, CON; IBM vs CON: p= 0.8). Hematopoietic recovery in the IBM and CON groups were similar. Leukocytes recovery (>1.0*109/l) occurred at median d+11 (range: d+10 - d+16, IBM) and d+10 (range: d+9-d+12, CON; IBM vs CON: p=0.3). Median leukocytes nadirs amounted to 0.23*109/l (IBM) and 0.28*109/l (CON; IBM vs CON: p=0.3) and median duration of leukopenia (<1.0*109/l) were 6 days (range: 5.0–11.0, IBM) and 4 days (range: 3.0–6.0, CON; IBM vs CON: p=0.1). Median platelet nadir after IBMT was 10.0*109/l (range: 0.0 - 25.0*109/l) and 6.0*109/l (range: 3.0-15.0*109/l, CON; IBM vs CON: p=0.8). Period of thrombocytopenia (≤50.0*109/l) lasted for 12 days in both groups (p=0.7). Chimerism analyses showed an early and fast increase in donor chimerism in both groups. The PBMC donor chimerism at d+14, d+28 and d+56 were 46% (range: 30-53%), 57% (range: 40-73%), 64% (range: 60-83%) for IBM. Results in CON were 37% (range: 17-93%), 60% (range: 49-100%), 57% (range: 40-100%) (IBM vs CON, p=n.s. (all time points)). The G chimerism values at that specific points were 95% (range: 53-100%), 100% (range: 53-100%), 96% (range: 88-100%) for IBM and 100% (range: 93-100%), 99% (range: 92-100%), 98% (range: 93-100%) for CON (IBM vs CON, p=n.s. (all time points)). Primary goal of the study was the feasibility of the IBM approach. Ethics regulations did not allow to use weak grafts (≤2.0*106/kg) intentionally. However, 4 animals received weak grafts (CON n=2, 1.0 and 2.0*106/kg; IBM n=2, 1.2 and 1.3 *106/kg). Of interest, comparing data of these dogs showed that durations of leukopenia were similar (median 10 days, both groups), but duration of thrombocytopenia were different (median 8 days, IBM vs 22 days, CON). Additionally, long term donor chimerism was higher in the IBM (median 80% PBMC, 100% G) vs CON (median 61% PBMC, 42% G). Conclusion: First, IBM HSCT is a feasible and effective method to deliver HSC directly into the bone marrow following RIC in a canine HSCT model. Second, our preliminary data suggest that IBM HSCT reveals advantageous engraftment differences in regards to platelet recovery and donor chimerism kinetics compared to the IV HSCT when grafts with low HSC numbers were infused. Follow up data of this study and future studies will have to clarify these observations further. Disclosures No relevant conflicts of interest to declare.

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Early Normalization of Serum Free Light Chain (FLC) Assays Correlates with Profound and Prolonged Responses in Newly Diagnosed Multiple Myeloma (MM)

Blood ◽

10.1182/blood-2018-99-116475 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1897-1897

Author(s):

Mercedes Gironella ◽

Alicia Senín ◽

Karla Vallejo ◽

Pamela Arenas ◽

Priyanka Raheja ◽

...

Keyword(s):

Conflicts Of Interest ◽

Autologous Transplantation ◽

University Hospital ◽

Rank Test ◽

Induction Treatment ◽

Early Prediction ◽

Newly Diagnosed ◽

Chemotherapy Treatment ◽

Hematopoietic Stem ◽

Prolonged Response

Abstract FLC is a recognized biomarker used for monitoring response and outcome of patients with amyloidosis and oligosecretory and non-secretory MM. Nevertheless, the role of FLC in the early prediction of response to the treatment in patients with gammopathies has not been fully ascertained. Against this background, we have evaluated the relationship between early FLC detection and the achievement of a deep and prolonged response after the end of the treatment in a series of patients diagnosed with MM and homogeneously treated in a single institution. Eighty-six newly diagnosed patients with MM between 2011 and January 2018 at the University Hospital Vall d'Hebron treated front-line with a bortezomib-based scheme were retrospectively analyzed. All patients had FLC levels measured by the Freelite® nephelometric assay at diagnosis, after the 2nd cycle of therapy, and at the end of treatment. Different parameters related to the FLC measurement were evaluated: normalization of the involved FLC (iFLC), ratio of involved/uninvolved FLCs (R_FLC)<10, reduction of R_FLC>95% compared to the baseline, and normalization of the ratio Kappa/lambda FLC (R_K/L). The predictive value of these parameters on the response after chemotherapy treatment was evaluated by using the Pearson´s exact test, and their impact on outcomes was analyzed by Kaplan Meier method using the long rank test for comparisons. The median age of the series at diagnosis was 69 years old (45-89). Forty-seven patients (55%) were considered candidate for autologous hematopoietic stem cell transplantation, therefore receiving induction treatment with the VTD combination (bortezomib-talidomide-dexametasone). In contrast, 39 patients (45%) were not candidate for autologous transplantation and were treated with MPV (melfalan-prednisone-bortezomib). The involved Ig was IgG in 54.7% of cases, IgA in 18.6%, IgD in 1.2% and IgM in 1.2%. Twenty-four percent of patients were diagnosed with MM of light chains (12% kappa and 12% lambda), whereas only 3 patients were diagnosed as having a oligosecretory MM. Twenty-nine percent of the cases were ISS III, 33% had increased serum LDH levels, and 79% showed immunoparesis. The kappa FLC mean at diagnosis was 1603.61 mg/dL (0.06 -36100 mg/dL) and lambda FLC was 1104 mg/dL (0.05-26500 mg/dL). Kappa FLC mean after 2nd cicle was of 192.14 mg/dL (1,61-6430 mg/dL) and lambda FLC was 61.41 mg/dL (0.05-1434 mg/dL). Thrirty-seven percent of patients obtained a profound response (≥VGPR) after the 2nd cycle of therapy, being this percentage increased to 63% of patients at the end of the chemotherapy treatment. Alongside this, the normalization of the iFLC was observed after the 2nd cycle of treatment in 44% of patients, the normalization of the R_K/L in 42%, R_FLC<10 in 70% of patients, and a reduction of R_FLs>95% was observed in 57% of patients. The great majority (80-87%) of patients attaining the normalization of any of these parameters after the 2nd cycle experienced a response ≥VGPR at the end of the treatment (table 1). With a median follow-up of 28.2 months (7-84 months), the overall PFS of the series was of 26.7 months. Of note, median PFS was of 40.3 months for patients who achieved the normalization of the iFLC after the 2nd cycle vs. 24.6 months for those who did not (p=0.047) (figure 1). Moreover, PFS was 27.3 months for those who had R_FLC<10 vs. 23 months for those with R_FLC≥10 (p=0.042). Finally, patients with reduction of R_FLC>95% exhibited a trend for a longer PFS (40.3 vs. 23.5 months) (p=0.09), as those patients with normalization of R_K/L who presented a PFS of 40.3 vs. 26.5 months (p=0.099). In conclusion, patients with normalization of different parameters related to FLC at 2 months of the onset of treatment exhibit a deeper and prolonged response to bortezomib-based chemotherapies, suggesting that this assessment could be of paramount interest in the early prediction of outcomes in patients with MM receiving treatment. Therefore, early FLC determinations should be incorporated into prospective clinical trials to validate these observations. Disclosures No relevant conflicts of interest to declare.

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Preliminary Results of the Flugaza Trial: A Phase III Randomized, Open Label Study Comparing Azacytidine Versus Fludarabine and Cytarabine (FLUGA Scheme) in Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v128.22.4036.4036 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4036-4036

Author(s):

Pau Montesinos ◽

Susana Vives ◽

Maria P Martinez-Sanchez ◽

Juan Bergua ◽

Lorenzo Algarra ◽

...

Keyword(s):

Elderly Patients ◽

Median Duration ◽

Outpatient Treatment ◽

Response Rate ◽

Conflicts Of Interest ◽

White Blood Cells ◽

Early Mortality ◽

Phase Iii ◽

Treatment Schedule ◽

Newly Diagnosed

Abstract Introduction: Current recommendations for the treatment of AML in newly diagnosed elderly patients (≥ 65 years) include different therapeutic options (intensive or semi-intensive chemotherapy, low-dose chemotherapy, hypomethylating agents, and supportive care). Regardless of the selected treatment, the results are disappointing because of low overall survival (OS) rates and significant toxicity. Objectives: The primary objective of FLUGAZA trial is to compare the 1-year-OS in 350 patients aged ≥ 65 years diagnosed with AML assigned to azacytidine (n=175) or FLUGA (n=175) arms. Here we present the results of a pre-planned interim safety analysis for both outpatient treatment regimens. Methods Inclusion criteria: Patients diagnosed with de novo or secondary AML according to WHO classification (except for APL), previously untreated, age ≥ 65 years, ECOG <4. Randomization arms (1:1): azacytidine (AZA) (75 mg/m2 SC days 1-7) and FLUGA (fludarabine 40 mg/m2 PO days 2-6, cytarabine 75 mg/m2 SC days 2-6, filgrastim 5 µg/Kg SC days 1-3), cycles of 28 days. The treatment schedule consisted of 3 induction cycles (C1, C2, C3), 6 consolidation cycles and a maintenance treatment until relapse or progression. FLUGA was reduced in patients older than 75 years and filgrastim in the FLUGA arm was omitted when white blood cells (WBC) were > 25 x109/L. Concomitant use of hydroxyurea was allowed in the AZA arm if WBC was between 15 and 50 x109/L. In patients with more than 50 x109/L WBC assigned to the AZA arm, the first induction cycle was FLUGA. An interim analysis to assess myelotoxicity, early mortality and response rate was planned in the trial when the last of the first 100 randomized patients completed the first 3 induction cycles. Results: From October 2014 to April 2016, 162 patients were enrolled in 26 Spanish centers from the PETHEMA group. Of them, 22 patients were screen failure and 16 patients did not receive the assigned treatment. The first 100 patients treated were analyzed (58 patients were assigned to AZA arm and 42 to FLUGA arm). Baseline characteristics are shown in Table 1. Median age was 75 [65;90] years in AZA arm vs. 77 [65;88] years in FLUGA arm; 36 (62%) vs. 19 (45%) males. Five patients from AZA arm (n=58) received the first cycle of FLUGA because of WBC > 50 x109/L. Outcomes: overall response rate (CR+CRu+PR) based on the best response accumulated with 3 cycles of treatment was 62% in the AZA arm and 57% in the FLUGA arm. CR+CRu was achieved in 14 patients (24%) from AZA arm and 15 (36%) from FLUGA arm. Early mortality rate (8 weeks) was 14% in AZA and 22% in FLUGA arm. Toxicities: there were no differences in hospitalization and non-hematological ≥ G3 serious adverse events (SAEs) between both arms. Overall, 71 patients (71%), 61 out of 79 (77%) vs. 41 out of 64 (64%) patients, developed neutropenia (< 0.5 x x109/L) after C1, C2 and C3, respectively. Median duration of neutropenia in the AZA arm was 14 days (6;40), 21 days (4;95) and 18 days (1;45) after in C1, C2 and C3, respectively, vs. 15 days (4;33), 15 days (3;36) and 20 days (7;41) after C1, C2 and C3, respectively, in the FLUGA arm (no statistically significant differences). Eighty-one (81%), 55 out of 79 (70%) vs. 40 out of 64 (62%) patients, developed thrombocytopenia (< 50 x109/L) after C1, C2 and C3, respectively. Median duration of thrombocytopenia was 14 days (5;29) after C1, 18 days (4;88) after C2 and 14 days (7;25) after C3 in the AZA arm; vs. 16 (3;63), 20 (6;42) and 13 days (7;56) after C1, C2 and C3, respectively, in the FLUGA arm (NS). Conclusions: Outpatient treatment with AZA or FLUGA was feasible. Both treatment arms showed a similar rate of early mortality and relatively low CR/CRu rates. The study is currently enrolling patients until the planned accrual goal (350 patients) to assess the primary end-point (1-year OS). The study is registered at www.ClinicalTrials.gov as NCT02319135. Disclosures No relevant conflicts of interest to declare.

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