Intensive Induction Therapy Research Articles

Abstract B146: Next-generation dendritic cell vaccination in postremission therapy of AML: Results of a clinical phase I trial

Abstract Postremission therapy for acute myeloid leukemia (AML) is critical for elimination of minimal residual disease (MRD). In patients not eligible for allogeneic stem cell transplantation, alternative treatment options are needed. Therapeutic vaccination with autologous dendritic cells (DCs) loaded with leukemia-associated antigens (LAAs) is a promising treatment strategy to induce anti-leukemic immune responses and to eradicate chemorefractory cells. We have developed a GMP-compliant 3-day protocol including a TLR7/8 agonist to differentiate monocytes of intensively pretreated AML patients into next-generation DCs. A phase I proof-of-concept study (n=6) was completed using next-generation DCs as postremission therapy of AML patients with a non-favorable genetic risk profile in CR after intensive induction therapy (NCT01734304), and we have already started enrollment into a phase II trial building on these results. DCs are loaded with ivt-RNA encoding the LAAs WT1 and PRAME as well as CMVpp65 as adjuvant and surrogate antigen. Patients are vaccinated intradermally with 5x106 DCs of each antigen species up to 10 times within 26 weeks. The primary endpoint of the phase I trial is feasibility and safety of the vaccination. Secondary endpoints are immunological responses and disease control. In total, 10 patients have been enrolled into the phase I/II trial. With two screening failures, DCs of sufficient number and quality were generated from leukapheresis in 7/8 cases. DC analysis demonstrated a positive costimulatory profile, secretion of IL-12p70, migration towards a chemokine gradient, antigen processing and presentation and activation of specific T cells in vitro. 5 patients have completed the vaccination schedule; the 6th patient has received 4/10 vaccinations. We observed delayed-type hypersensitivity (DTH) responses at the vaccination site in 5/5 patients, accompanied by slight erythema and indurations at the injection site, but no grade III/IV toxicities. Multimer analysis revealed the induction of antigen-specific T cell responses in 3/3 patients tested. We detected an increase of WT1-specific T cells in one patient and strong inductions of CMVpp65-specific T cells in two CMV-seronegative patients. TCR repertoire analysis by next-generation sequencing revealed an enrichment of particular clonotypes at DTH sites. In an individual treatment attempt, we treated one patient with impending relapse with a combination of DC vaccination and 5-azacytidine, resulting in MRD conversion. From the results of our phase I trial, we conclude that vaccination with next-generation DCs in AML is feasible and safe and induces leukemia-specific immune responses in vivo. The protocol is continued to be studied in an ongoing phase II trial. Citation Format: Felix S. Lichtenegger, Frauke M. Schnorfeil, Thomas Köhnke, Torben Altmann, Veit Bücklein, Andreas Moosmann, Monika Brüggemann, Beate Wagner, Wolfgang Hiddemann, Iris Bigalke, Gunnar Kvalheim, Marion Subklewe. Next-generation dendritic cell vaccination in postremission therapy of AML: Results of a clinical phase I trial. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B146.

Diagnostic Dilemma in Appendiceal Mucormycosis: A Rare Case Report.

Appendiceal mucormycosis is a rare life-threatening infection seen in immunocompromised patients. It is usually seen in chemotherapy induced neutropenia in patients with hematological malignancies. Clinically, the symptoms and signs may be masked due to ongoing corticosteroids. The condition may mimic bacterial appendicitis and the less serious condition, typhlitis. The disease demands prompt surgical debulking and aggressive antifungal treatment. However, surgery is delayed due to the poor performance status and severe neutropenia. This may lead to perforative peritonitis and further dissemination. The survival rates of such disease are dismal. Unfortunately, the diagnosis may be confirmed only on histological examination of the surgically excised tissue. Very few cases have been reported so far. We present here once such a fatal case of appendiceal mucormycosis in a 14-year-old boy who was immunosuppressed due to intensive induction therapy for Acute Myeloblastic Leukemia.

Patients with "Single-Hit" but Not MYC -Amplified Non-Burkitt High-Grade B Cell Non-Hodgkin Lymphomas Experience Poor Survival Outcomes and May Benefit from Intensive Induction Therapy

Patients with "Single-Hit" but Not MYC -Amplified Non-Burkitt High-Grade B Cell Non-Hodgkin Lymphomas Experience Poor Survival Outcomes and May Benefit from Intensive Induction Therapy

Next-Generation Dendritic Cell Vaccination in Postremission Therapy of AML: Results of a Clinical Phase I Trial

Postremission therapy for acute myeloid leukemia (AML) is critical for elimination of minimal residual disease (MRD). In patients not eligible for allogeneic stem cell transplantation, alternative treatment options are needed. Therapeutic vaccination with autologous dendritic cells (DCs) loaded with leukemia-associated antigens (LAAs) is a promising treatment strategy to induce anti-leukemic immune responses and to eradicate chemorefractory cells. We have developed a GMP-compliant 3-day protocol including a TLR7/8 agonist to differentiate monocytes of intensively pretreated AML patients into next-generation DCs.A phase I/II proof-of-concept study has been initiated using next-generation DCs as postremission therapy of AML patients with a non-favorable genetic risk profile in CR after intensive induction therapy (NCT01734304). DCs are loaded with in vitro transcribed RNA encoding the LAAs WT1 and PRAME as well as CMVpp65 as adjuvant and surrogate antigen. Patients are vaccinated intradermally with 5x106 DCs of each antigen species up to 10 times within 26 weeks. The primary endpoint of the phase I/II trial is feasibility and safety of the vaccination. Secondary endpoints are immunological responses and disease control.Based on the safety and toxicity profile of the phase I trial (n=6), phase II has been initiated. In total, 10 patients have been enrolled into the study. DCs of sufficient number and quality were generated from leukapheresis in 8/9 cases. DCs exhibited an immune-stimulatory profile based on high surface expression of positive costimulatory molecules, the capacity to secrete IL-12p70, the migration towards a chemokine gradient and processing and presentation of antigen. 5 patients have completed the vaccination schedule; the 6th and 7th patient have received 7/10 and 4/10 vaccinations, respectively. We observed delayed-type hypersensitivity (DTH) responses at the vaccination site in 6/6 patients, accompanied by slight erythema and indurations at the injection site, but no grade III/IV toxicities. TCR repertoire analysis by next-generation sequencing revealed an enrichment of particular clonotypes at DTH sites. Limited by HLA restriction, we have so far analyzed 4 patients by multimer staining. All of them mounted DC vaccination-specific T cell responses: We detected an increase of WT1-specific T cells in one patient and strong expansion/induction of CMVpp65-specific T cells in one CMV-seropositive and two CMV-seronegative patients. In an individual treatment attempt, an enrolled patient with impending relapse was treated with a combination of DC vaccination and 5-azacytidine, resulting in MRD conversion. Long-term disease control and immunological responses are studied in the ongoing phase II trial.We conclude that vaccination with next-generation LAA-expressing DCs in AML is feasible, safe and induces anti-leukemia-specific immune responses in vivo. DisclosuresSubklewe:AMGEN Research (Munich): Research Funding.

Midostaurin in Combination with Intensive Induction and As Single Agent Maintenance Therapy after Consolidation Therapy with Allogeneic Hematopoietic Stem Cell Transplantation or High-Dose Cytarabine (NCT01477606)

Background: Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in roughly 25% of younger adult patients (pts) with acute myeloid leukemia (AML), implicating FLT3 as a potential target for kinase inhibitor therapy. The multi-targeted kinase inhibitor midostaurin shows potent activity against FLT3 as a single agent but also in combination with intensive chemotherapy.Aims: To evaluate the feasibility and efficacy of midostaurin in combination with intensive induction therapy and as single agent maintenance therapy after allogeneic hematopoietic stem cell transplantation (alloHSCT) or high-dose cytarabine (HIDAC).Methods: The study includes adult pts (age 18-70 years (yrs)) with newly diagnosed FLT3-ITD positive AML enrolled in the ongoing single-arm phase-II AMLSG 16-10 trial (NCT: NCT01477606). Pts with acute promyelocytic leukemia are not eligible. The presence of FLT3-ITD is analyzed within our diagnostic study AMLSG-BiO (NCT01252485) by Genescan-based fragment-length analysis (allelic ratio >0.05 required to be FLT3-ITD positive). Induction therapy consists of daunorubicin (60 mg/m², d1-3) and cytarabine (200 mg/m², continuously, d1-7); midostaurin 50 mg bid is applied from day 8 onwards until 48h before start of the next treatment cycle. A second cycle is optional. For consolidation therapy, pts proceed to alloHSCT as first priority; if alloHSCT is not feasible, pts receive three cycles of age-adapted HIDAC in combination with midostaurin from day 6 onwards. In all pts maintenance therapy for one year is intended. This report focuses on the first cohort of the study (n=149) recruited between June 2012 and April 2014 prior to the amendment increasing the sample size; the amendment to the study is active since October 2014.Results: At study entry patient characteristics were median age 54 years (range, 20-70, 34% ≥ 60 yrs); median white cell count (WBC) 48.4G/l (range 1.1-178G/l); karyotype, n=103 normal, n=3 t(6;9), n=2 t(9;11), n=20 intermediate-2 and n=7 high-risk according to ELN recommendations, n=14 missing; mutated NPM1 n=92 (62%). Data on response to first induction therapy were available in 147 pts; complete remission (CR) 58.5%, partial remission (PR) 20.4%, refractory disease (RD) 15% and death 6.1%. A second induction cycle was given in 34 pts. Overall response after induction therapy was CR 75% and death 7.5%. Adverse events 3°/4° reported during the first induction cycle were most frequently gastrointestinal (n=34) and infections (n=81). During induction therapy midostaurin was interrupted, dose-reduced or stopped in 55% of the pts. Overall 94 pts received an alloHSCT, 85 in first CR (n=65 age<60 yrs, n=20 age ≥60 yrs) and 9 pts after salvage outside the protocol or after relapse (n=70 from a matched unrelated and n=24 from a matched related donor). In pts receiving an alloHSCT within the protocol in median 2 chemotherapy cycles were applied before transplant (range 1-4) and the cumulative incidence of relapse and death at 12 months were 9.2% (SE 3.3%) and 19.5% (SE 4.8%). Maintenance therapy was started in 52 pts, 40 pts after alloHSCT and 12 pts after HIDAC. Only 4 adverse events 3°/4° were attributed to midostaurin. First analyses revealed a low cumulative incidence of relapse irrespective of the FLT3-ITD mutant to wildtype ratio (<0.5 versus ≥0.5) in patients proceeding to alloHSCT with 12% and 5% as well as for those after HIDAC consolidation with 28% and 29%, respectively.Conclusions: The addition of midostaurin to intensive induction therapy and as maintenance after alloHSCT or HIDAC is feasible and compared to historical data may be most effective in those patients with a high FLT3-ITD mutant to wildtype ratio. DisclosuresSchlenk:Novartis: Honoraria, Research Funding. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Götze:Celgene Corp.: Honoraria; Novartis: Honoraria.

Inferior Outcomes with Intensive AML Induction Therapy in Patients Age 70 or Greater Compared to Age 60-69

Background: The median age of diagnosis for acute myeloid leukemia (AML) is between age 65 and 70. While advances in therapy and supportive care in the past several decades has significantly improved outcomes in younger patients, the prognosis in elderly AML patients, defined as age 60 or greater, remains dismal. In addition, many elderly patients are unable to receive such aggressive therapy due to increased treatment-related mortality and poorer clinical response. There remains great interest in identifying factors that are associated with both beneficial and detrimental outcomes in this patient population.Methods: This was a retrospective analysis conducted at Moffitt Cancer Center. The primary study objective was to compare the incidence of 30-day mortality of patients aged 60-69 years vs. patients 70 years or older with newly diagnosed AML who received intensive remission induction chemotherapy. Secondary endpoints included 60-day mortality, overall survival (OS), complete response rate (CR), receipt of allogeneic hematopoietic stem cell transplant, rate of infection, cardiac complications, major organ failure, ICU transfer, and any other treatment-related complications. Baseline patient characteristics at diagnosis were summarized using descriptive statistics including mean, median, standard deviation, and range for continuous measures and proportions and frequencies for categorical measures. The primary outcome was assessed via chi-squared analysis. Assuming treatment-related mortality is 5% in the younger patients and 15% in patients > 70 years old, with a 2-sided p-value of 0.05, a sample size of 300 would provide a power of 0.83 to detect this 10% difference in mortality. Overall survival was estimated using the Kaplan-Meier method, and compared using a log-rank test. Univariate and multivariate analyses using Cox-Regression models were conducted to identify factors affecting OS.Results: A total of 246 patients with newly diagnosed AML between age 60-69 (n=132) and 70 or greater (n=114) who underwent initial remission-induction chemotherapy between July 2009 and July 2014 were identified and included in this analysis. Background characteristics and known factors that affect CR and OS such as overall risk category and performance status were well matched between groups. Sixty-four (56%) patients in the older and 62 (47%) patients in the younger group received 7+3 induction chemotherapy, whereas 41 (36%) in the older and 50 (38%) in the younger group received cladribine-based regimens. The remainder of patients received clinical trial induction chemotherapy. Twenty-three (17.4%) of patients in the younger patient group underwent immediate re-induction chemotherapy, compared to 8 (7%) patients in the older group (p=0.02).Thirty day mortality rate was 6.8% (9) in the younger group and 14% (16) in the older group (p=0.062). By day 60 after initiation of induction chemotherapy, 13.6% (18) and 23.7% (27) of patients in the younger and older cohorts, respectively, were deceased (p=0.031). No difference was noted in infection rate, ICU transfer, major organ failure, percentage of patients intubated, incidence of tumor lysis syndrome, or initiation of parenteral nutrition.Seventy-nine (59.8%) patients in the younger arm achieved CR, compared to 51 (44.7%) patients in the older arm (p=0.003). Median OS was 10.4 months and 8.3 months in the younger and older group respectively (p=0.002). Significantly more patients in the younger group went on to receive stem cell transplant. Multivariate analysis of the composite group revealed age >75, risk category, prior therapy with hypomethylating agents, and number of comorbidities were predictors of poorer survival.Conclusions: The presented study demonstrates that intensively-treated patients age ≥70 have an increased early treatment-related mortality, similar treatment-related morbidity, and a lower incidence of CR and OS compared to patients age 60-69. Additionally, prior hypomethylator use, risk category and comorbidities contribute to poorer survival. These observations give further insight into the role of intensive remission chemotherapy in an elderly AML patient population.Table 1Multivariable Analysis Overall Survival (p = <0.05)Hazard Ratio95% CIAge >751.51.06-2.20Risk Category1.11.01-1.16Prior Hypomethylator1.61.17-2.12No. of Comorbidities1.11.04-1.20 [Display omitted] DisclosuresOff Label Use: Cladribine for use in acute myeloid leukemia.

The Prognostic Relevance of Comprehensive Risk Score Is Modulated By Therapy: Analysis of 292 Acute Myeloid Leukemia Patients Registered at the Genova Acute Leukemia Registry (REGAL)

Background, methods and aims of the study.It is widely established that the prognosis of patients with acute myeloid leukemia (AML) is related to clinical (age, denovo or secondary leukemia, presence of comorbidities), cytogenetic and molecular (e.g. FLT3-ITD, NPM1 gene mutation.) factors. We have developed a Comprehensive Risk Score (CRS) identifying three prognostic subgroups with favorable (low risk karyotype or intermediate karyotype + mutations of NPM1 gene without FLT3-ITD), unfavorable (high risk cytogenetics or FLT3-ITD without NPM1 mutation or secondary AML) and intermediate (including all the other patients not belonging to previous groups) prognosis. The clinical utility of CRS was tested on a cohort of 292 AML patients included in the REGAL registry, a regional Italian registry that was established in October 2010 at the University of Genoa.Results.Analysis of age distribution confirmed the increased incidence of AML in patients older than 60 years (n. 182, 62.4%). Patients with de novo or secondary AML were 210 (71.9%) and 82, (28.1%) respectively. Patients with significant and often multiple comorbidities at diagnosis were 131 (44.8%). Seventeen patients (6%) received only supportive therapy, 217 (74.3%) intensive induction regimens (mainly FLAG-Ida and 3+7), including 96% of patients with age below 60 years and 61% of those over the age of 60 years. Therapy with hypomethylating agents (azacitidine and decitabine) was given to 31 patients (10.6%).In the whole cohort of patients 24 months projected survival (OS) was 66% among 62 patients defined as low risk according CRS (median not reached), 37,9% among 118 intermediate risk patients (median 13.8 months) and 12,7% in 112 patients included in the unfavorable risk group (median survival 4.8 months) (p =0.000, Fig. 1).In patients aged younger than 60 years, OS of favorable and intermediate risk groups were similar (77% and 72% in 39 low risk and in 44 intermediate risk patients, respectively), whereas the outcome of 27 high risk patients was worse (OS 28.2%, median survival of 10,3 months, p 0.0001). In the group of elderly patients (> 60 years) the outcome of the intermediate group was rather similar to that observed in the poor risk group (OS 16% and 7% in 74 intermediate and in 85 poor risk patients, respectively, p n.s). On the contrary OS of 23 favorable risk patients was good (49%, p = 0.0015).Twenty-nine patients have actually received an allogeneic bone marrow transplant (BMT) during first CR (66% of 44 with indication) and 14 in second or third CR. The sources of stem cells have been HLA-identical and haploidentical sibling in 45% and 50% of patients, respectively.Discussion and conclusions.Our study suggests that the predictive value of CRS is clearly affected by the therapeutic strategy. Whereas the score allows the stratification of the whole cohort of patients in three groups with different outcome, in younger fit patients a more intensive therapeutic approach, such as the FLAG-IDA regimen and a wider use of allogeneic bone marrow transplantation made possible by the use of haploidentical donors, results in the super-imposable prognosis between favorable risk and intermediate risk patients.However, the same intensive approach cannot overcome the unfavorable features of the majority of high risk patients.In the elderly group median age and comorbidities prevent patients from receiving intensive induction therapy. Therefore, intermediate and unfavorable risk patients show a similar poor outcome. In elderly patients the achievement of a good outcome is related to disease status (denovo AML), favorable cytogenetic and molecular features, good performance status and administration of intensive induction and consolidation treatment, including BMT in selected cases. [Display omitted] DisclosuresCarella:Seattle Genetics Inc.: Research Funding.

Liberal Vs. Restrictive Transfusion Thresholds in Leukemia Patients: A Feasibility Pilot Study

Transfusion of red blood cells (RBCs) is vitally important for the care of patients (pts) undergoing myelosuppressive therapy for acute leukemia (AL). At diagnosis and before bone marrow recovery, RBCs are given liberally with hemoglobin (Hb) transfusion triggers of 8-9 g/dL or higher, often with two RBC units given at a time. Research in a variety of non-oncologic settings suggests that lower Hb triggers (7-8 g/dL) do not increase mortality whereas higher Hb triggers (9 g/dL) may increase mortality. For pts with hematologic malignancies, the ideal Hb threshold is unknown. Also, there is literature to suggest that higher Hb values force platelets to the periphery of capillaries and reduce bleeding events. A study of red cell triggers in pts with thrombocytopenia (as in AL) is important as we may not be able to rely on trigger data from others in this setting. This feasibility study was designed to determine whether a randomized trial of Hb triggers could be performed and what challenges may be encountered with this select population.In this prospective randomized study, we enrolled adult pts with AL (myeloid and lymphoid) undergoing intensive induction therapy to evaluate both patient and physician tolerance for a transfusion threshold of 7g/dL (LOW) compared to the standard threshold of 8g/dL (HIGH), as well as operationalize transfusion to a single unit per episode. Pts were randomized with a 2:1 ratio of LOW threshold to HIGH threshold. Pts were ineligible if there was clinical concern for acute coronary syndrome or active blood loss. Pts were monitored from the study enrollment date through the next marrow evaluation after completion of induction therapy. Vital status at Day 60, accrual rate, and safety endpoints (mortality, length of stay, infection, fatigue scores, renal, respiratory, thrombotic, bleeding events) were monitored. Total transfusions, length of inpatient stay, and percentage of pts who crossed over to HIGH threshold for symptomatic reasons were also monitored.Between April 15, 2014 and July 23, 2015, 162 acute leukemia pts would have been eligible for this trial. Of the eligible pts, 112 (69%) were approached and 90 (of planned 90) have enrolled to date. Twenty-two pts (19.6%) of those offered the trial declined. Seventy-four pts are currently evaluable for response (13 pts have not been on-study long enough to evaluate and 3 pts are not eligible for data analysis): 51 pts in LOW arm and 23 in HIGH arm. Interim data is shown in Table 1. In the LOW arm, three pts withdrew consent due to self-reported fatigue and one patient was removed by physician due to clinical scenario. Seventeen pts (33%) in the LOW arm and six pts (26%) in the HIGH arm were transfused outside their hemoglobin trigger without meeting criteria to discontinue the study. No deaths were attributable to Hb thresholds in this study. Significant bleeding events (Grade 3 or 4 by CTCAE 4.0) were comparable with 4 in LOW arm and 3 in HIGH arm. More minor bleeding events (Grade 1 or 2 by CTCAE 4.0) were higher in LOW (24 events) than in HIGH arm (15 events).Acute leukemia and its therapies carry a significant mortality risk and it is not clear how transfusion thresholds and number of PRBC units transfused impact this mortality. Furthermore, blood is an expensive and scarce resource. Without a clear benefit of higher Hb thresholds, the added risks and costs of transfusion may not be justified. This pilot study shows that both pts and leukemia physicians will tolerate randomization between Hb thresholds and there is not a signal for harm in either Hb threshold at present. Pts in the LOW arm receive fewer transfusions and do not experience higher fatigue scores nor increased significant bleeding events. Length of hospitalization was similar in both arms. This safety data will serve as a platform for a larger mortality study in leukemia and possibly additional studies in other oncologic diseases.Table 1LOWHIGHP valuePatients (n)51 (69%)23 (31%)Gender Male23 (45%)11 (48%)Median Age (Years)58630.35AML44 (86%)18 (78%)ALL5 (10%)5 (22%)APL2 (4%)0Patients Alive at Day 6046 (90%)21 (91%)Red Cell Transfusions in Units (Median)8 (IQR: 5)10 (IQR: 4)0.008*Platelet Transfusions in Episodes (Median)9 (IQR: 6.5)9 (IQR: 5)0.86Length of Stay (Median)35 (IQR: 10)36 (IQR: 15)0.72Fatigue Scale Score (Median)4.33 (IQR: 1)4.54 (IQR: 1.25)0.40AML: acute myeloid leukemia; ALL: acute lymphoid leukemia; APL: acute promyelocytic leukemia DisclosuresNo relevant conflicts of interest to declare.

Impact of oncogene rearrangement patterns on outcomes in patients with double-hit non-Hodgkin lymphoma.

Double-hit lymphomas (DHLs) are collectively defined as B-cell non-Hodgkin lymphomas harboring rearrangements of MYC as well as B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6). To the authors' knowledge, the impact of specific oncogene rearrangements on outcomes of patients with DHL who are treated with immunochemotherapy has not been previously described. The authors identified patients whose diagnostic tissue specimens underwent metaphase karyotyping or fluorescence in situ hybridization for MYC as well as both BCL2 and BCL6 rearrangements. Cohorts were defined by the presence (+) or absence (-) of rearrangements: MYC+/BCL2+/BCL6- (BCL2-DHL), MYC+/BCL2-/BCL6+ (BCL6-DHL), and MYC+/BCL2+/BCL6+ (triple-hit lymphoma; THL). A total of 117 patients were included in the current analysis (76 BCL2-DHL patients, 16 BCL6-DHL patients, and 25 THL patients). Compared with patients with BCL2-DHL, those with BCL6-DHL were more likely to be classified as having a non-germinal center cell of origin, presented with extranodal disease, and appeared to achieve higher rates of complete response despite receiving intensive induction therapy less frequently. However, patients with BCL6-DHL experienced a shorter median overall survival if achieving an initial complete response compared with patients with BCL2-DHL. Patients with THL experienced survival outcomes similar to those of patients with BCL2-DHL. Recognition of the specific oncogene rearrangements may be of prognostic value and potentially guide future therapeutic strategies for patients with DHL.

Sapacitabine in acute myelogenous leukemia

Introduction: The treatment of acute myelogenous leukemia remains challenging, especially in older adults or those unfit for intensive induction therapy or allogeneic stem cell transplant. Sapacitabine is a novel, rationally-designed, orally administered nucleoside analog that has shown promising activity in early clinical trials in acute myelogenous leukemia. Areas covered: This review covers the biochemical and pharmacologic properties of the drug with a focus on the clinical activity, safety and tolerability of sapacitabine in the treatment of acute myelogenous leukemia. Expert opinion: Sapacitabine is a promising orally administered drug in the treatment of acute myelogenous leukemia. While clinical data have failed to show significant benefit as a single agent, the drug has demonstrated clinical activity as monotherapy. Early clinical data has shown encouraging results in combinations with other agents.

Clinicopathologic features, management and outcomes of blastoid variant of mantle cell lymphoma: a Nebraska Lymphoma Study Group Experience

The objective of this retrospective study (N = 169) was to compare the overall survival (OS) of different subtypes of mantle cell lymphoma (MCL) treated by the Nebraska Lymphoma Study Group between 1984 and 2012. The overall response rate to various therapies including stem cell transplant (SCT) was similar (p = 0.44) between blastoid, diffuse and nodular subtypes. At 5 years, blastoid and diffuse subtypes had worse OS (overall p = 0.005) compared to nodular subtype. In multivariate analysis, the blastoid and diffuse subtypes had similar risk of death (p = 0.14) whereas the nodular subtype had a lower risk compared to blastoid (HR 0.48, 95% CI 0.27–0.87, p = 0.01). The use of SCT was associated with lower risk of death. In univariate analysis, blastoid subtype had better OS with intensive upfront therapy. In conclusion, the OS of blastoid subtype is worse than nodular MCL but may improve with the use of SCT and probably intensive induction therapy.

Management of Newly Diagnosed Acute Myeloid Leukemia in the Elderly: Current Strategies and Future Directions.

The incidence of acute myeloid leukemia (AML) increases with age, and the majority of cases occur in adults aged >55years. The prognosis of AML in older adults is generally poor; however, AML is a heterogeneous disease regardless of age, and prognosis depends on cytogenetic changes, genetic mutations, and patient characteristics. Several lines of evidence support offering treatment to the vast majority of older patients, and the survival benefit associated with this approach generally outweighs the risk of toxicity. Response and long-term survival using intensive induction regimens are significantly lower in older patients, although a small proportion of patients can achieve durable remissions. Selection of patients for intensive induction therapy requires comprehensive assessment of disease characteristics, performance status, and comorbidities. In unfit patients, options for treatment include hypomethylating agents, low-dose ara-C, or consideration of a clinical trial if available. The incorporation of novel therapies into treatment, such as FLT3 inhibitors and antibody-drug conjugates, offers significant promise in older patients, although, thus far, increased responses using novel agents have often not translated to improved survival outcomes. The development of reduced-intensity conditioning regimens and improvements in supportive care has increased the use of allogeneic stem cell transplant (ASCT) in older patients. Selection of patients for ASCT requires an estimation of the trade-off between toxicity and risk of relapse.

How I treat refractory and early relapsed acute myeloid leukemia

AbstractBetween 10% and 40% of newly diagnosed patients with acute myeloid leukemia (AML) do not achieve complete remission with intensive induction therapy and are therefore categorized as primary refractory or resistant. Few of these patients can be cured with conventional salvage therapy. They need to be evaluated regarding eligibility for allogeneic hematopoietic stem cell transplantation (HSCT) as this is currently the treatment with the highest probability of cure. To reduce the leukemia burden prior to transplantation, salvage chemotherapy regimens need to be employed. Whenever possible, refractory/relapsed patients should be enrolled in clinical trials as we do not have highly effective and standardized treatments for this situation. Novel therapies include tyrosine kinase inhibitors, small-molecule inhibitors (eg, for Polo-like kinase 1 and aminopeptidase), inhibitors of mutated isocitrate dehydrogenase (IDH) 1 and IDH2, antibody-based therapies, and cell-based therapies. Although the majority of these therapies are still under evaluation, they are likely to enter clinical practice rapidly as a bridge to transplant and/or in older, unfit patients who are not candidates for allogeneic HSCT. In this review, we describe our approach to refractory/early relapsed AML, and we discuss treatment options for patients with regard to different clinical conditions and molecular profiles.

Phase III randomized trial of volasertib combined with low-dose cytarabine (LDAC) versus placebo plus LDAC in patients aged ≥65 years with previously untreated, acute myeloid leukemia (AML) ineligible for intensive remission induction therapy

S194 228 Clinical description of acute promyelocytic leukemia (APL) patients receiving all-trans retinoic acid (ATRA) who develop pseudotumor cerebri: Incidence, diagnosis, outcomes, and recommendations for management Catherine C. Coombs, Lisa M. DeAngelis, James H. Feusner, Martin S. Tallman Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center; Department of Neurology, Memorial Sloan Kettering Cancer Center; Department of Hematology/Oncology, Children’s Hospital & Research Center

Integrated Genomic Profiling, Therapy Response And Survival in Adult Acute Myelogenous Leukemia

Purpose: Recurrent gene mutations, chromosomal translocations, and acquired genomic copy number aberrations (aCNA) have been variously associated with acute myelogenous leukemia (AML) patient outcome. However, knowledge of the co-occurrence of such lesions and the relative influence of different types of genomic alterations on clinical outcomes in AML is still evolving. Experimental Design: We performed SNP 6.0 array-based genomic profiling of aCNA/copy neutral loss-of-heterozygosity (cnLOH) along with sequence analysis of 13 commonly mutated genes on purified leukemic blast DNA from 156 prospectively enrolled non-FAB-M3 AML patients across the clinical spectrum of de novo , secondary, and therapy-related AML. Results: TP53 and RUNX1 mutations are strongly associated with the presence of SNP-A–based aCNA/cnLOH, while FLT3 and NPM1 mutations are strongly associated with the absence of aCNA/cnLOH. The presence of mutations in RUNX1 , ASXL1 , and TP53 , elevated SNP-A–based genomic complexity, and specific recurrent aCNAs predicted failure to achieve a complete response to induction chemotherapy. The presence of ≥1 aCNA/cnLOH and higher thresholds predicted for poor long-term survival irrespective of TP53 status, and the presence of ≥1 aCNA/cnLOH added negative prognostic information to knowledge of mutations in TET2 , IDH1 , NPM1 , DNMT3A , and RUNX1 . Results of multivariate analyses support a dominant role for TP53 mutations and a role for elevated genomic complexity as predictors of short survival in AML. Conclusions: Integrated genomic profiling of a clinically relevant adult AML cohort identified genomic aberrations most associated with SNP-A–based genomic complexity, resistance to intensive induction therapies, and shortened overall survival. Identifying SNP-A–based lesions adds prognostic value to the status of several recurrently mutated genes. Clin Cancer Res; 1–12. ©2015 AACR.

Integrated genomic profiling, therapy response, and survival in adult acute myelogenous leukemia.

Recurrent gene mutations, chromosomal translocations, and acquired genomic copy number aberrations (aCNA) have been variously associated with acute myelogenous leukemia (AML) patient outcome. However, knowledge of the co-occurrence of such lesions and the relative influence of different types of genomic alterations on clinical outcomes in AML is still evolving. We performed SNP 6.0 array-based genomic profiling of aCNA/copy neutral loss-of-heterozygosity (cnLOH) along with sequence analysis of 13 commonly mutated genes on purified leukemic blast DNA from 156 prospectively enrolled non-FAB-M3 AML patients across the clinical spectrum of de novo, secondary, and therapy-related AML. TP53 and RUNX1 mutations are strongly associated with the presence of SNP-A-based aCNA/cnLOH, while FLT3 and NPM1 mutations are strongly associated with the absence of aCNA/cnLOH. The presence of mutations in RUNX1, ASXL1, and TP53, elevated SNP-A-based genomic complexity, and specific recurrent aCNAs predicted failure to achieve a complete response to induction chemotherapy. The presence of ≥1 aCNA/cnLOH and higher thresholds predicted for poor long-term survival irrespective of TP53 status, and the presence of ≥1 aCNA/cnLOH added negative prognostic information to knowledge of mutations in TET2, IDH1, NPM1, DNMT3A, and RUNX1. Results of multivariate analyses support a dominant role for TP53 mutations and a role for elevated genomic complexity as predictors of short survival in AML. Integrated genomic profiling of a clinically relevant adult AML cohort identified genomic aberrations most associated with SNP-A-based genomic complexity, resistance to intensive induction therapies, and shortened overall survival. Identifying SNP-A-based lesions adds prognostic value to the status of several recurrently mutated genes.

Health care utilization and end-of-life care for older patients with acute myeloid leukemia.

Health care utilization in older adults (age ≥60 years) with acute myeloid leukemia (AML) has not been well studied. We conducted a retrospective analysis of 330 consecutive older patients who were diagnosed with AML between May 1, 2005 and December 23, 2011, at 2 hospitals in Boston to examine their health care utilization and end-of-life care. Using multivariable logistic and linear regression models adjusting for covariates, we also compared health care utilization between patients who received intensive induction chemotherapy (n = 197; cytarabine/ anthracycline combination) versus nonintensive chemotherapy (n = 133; single-agent therapy). The median number of hospitalizations for the entire cohort was 4.2 (range, 1-18 hospitalizations). Patients who died spent a mean of 28.3% of their life after diagnosis in the hospital and 13.8% of their life attending outpatient clinic appointments. Although the majority of patients (87.9%) died during the 2-year follow-up period, a minority received palliative care (16.2%) or hospice (23.1%) services. Within 30 days of death, 84.5% of patients were hospitalized, and 61% died in the hospital. Among the patients who died, those who received intensive induction therapy (vs nonintensive therapy) spent 30% more of their life after diagnosis in the hospital (P < .0001) and were less likely to receive hospice services (odds ratio, 0.45; P = .05). The current findings highlight the intensity of health care utilization among older patients with AML, regardless of treatment modality. Despite the poor prognosis, palliative care and hospice services are rarely used. Future work should study novel health care delivery models to optimize care throughout the course of illness and at the end of life.

The fate of patients with acute myeloid leukemia not undergoing induction chemotherapy.

Advances in chemotherapy for acute myeloid leukemia (AML) have resulted in the exclusion of patients not undergoing induction chemotherapy from research studies. To examine in detail the clinical experience of such patients, we retrospectively analyzed the outcomes of consecutive patients diagnosed with AML at our hospital from 2004 to 2012. Of 158 AML patients, 43 (27 %) did not undergo induction chemotherapy. Their median survival duration was 1.5 months, with 11, six, and four patients surviving more than 3, 6, and 12 months, respectively. As expected, their survival was worse than that of those treated with intensive or less-intensive induction therapy (14, 74, and 47 % at 1 year, and 0, 40, and 10 % at 4 years, respectively). Low white blood cell count at AML diagnosis and prior history of myelodysplastic syndrome were significantly associated with longer survival. Our findings suggest that modern supportive care measures do not prolong survival for AML patients not undergoing induction chemotherapy, although certain patients show relatively long survival. These data should prove helpful in discussing treatment pathways with patients for cases in which palliative or supportive therapy alone may be a viable treatment option.

Satisfactory outcome after intensive chemotherapy with pragmatic use of minimal residual disease (MRD) monitoring in older patients with Philadelphia-negative B cell precursor acute lymphoblastic leukaemia: a Swedish registry-based study.

The introduction of minimal residual disease (MRD) monitoring, in the Swedish national guidelines for acute lymphoblastic leukaemia, was evaluated in 35 patients aged 46-79 years (median 61), who were diagnosed from 2007 to 2011 and treated with high-intensity, block-based chemotherapy (ABCDV/VABA induction). Both a high complete remission rate (91 %) and acceptable overall survival (OS) rate (47 %) at 5 years were achieved. MRD by flow cytometry was measured in 73 % of the patients reaching complete remission after the first course, but was omitted by the clinicians for eight patients who were either over 70 years of age or already met conventional high-risk criteria. Factors negatively influencing OS were age over 65 years and WHO status ≥2. MRD < 0.1 % after induction had positive impact on continuous complete remission but not on OS. Only five patients were allocated to allogeneic haematopoietic stem cell transplantation in first remission, mainly due to conventional high risk factors. Thus, use of intensive remission induction therapy is effective in a selection of older patients. In a population for whom the possibilities of treatment escalation are limited, the optimal role of MRD monitoring remains to be determined.

Impact of Donor Type on Outcome after Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia Patients: Analysis of the German-Austrian Acute Myeloid Leukemia Study Group (AMLSG)

Background:Despite recent advances in identifying novel molecular targets in AML patients, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT) still remains a cornerstone of AML therapy. However, outcome of HSCT depends on the availability of a donor and the donor type. Prior studies comparing HSCT from HLA-matched related donors (MRD) with matched unrelated donors (MUD), demonstrated conflicting results with regards to outcome. These conflicting results might be attributed to the genetic heterogeneity of AML.Aims:To analyze outcome with respect to donor type of 952 AML patients who received HSCT in first complete remission (CR) and were treated within prospective AMLSG trials.Methods:Within the AMLSG trials conducted between 1993 and 2013, of a total of 4991 patients (excluding acute promyelocytic leukemia), 3408 (2744 younger (<61 years old), 664 older (≥61 years old)) patients achieved a first CR after intensive double induction therapy. Of these, 867 (31%) younger and 85 (13%) older patients received HSCT in first CR. Distributions of donor types were 511 matched related donors (MRD), 435 matched unrelated donors (MUD) and 6 haplo-identical donors. The latter were grouped together with MUD.Results:Distributions of donor type over time are illustrated in table 1 indicating two clear trends with increasing numbers of MUD transplants and increasing median age in MUD- and MRD-transplants in recent years. There was no significant difference in overall survival, cumulative incidence of relapse (CIR) and death (CID) all estimated at 4 years according to the three time periods for MRD (p=0.56, p=0.15, p=0.10, respectively) and MUD (p=0.27, p=0.20, p=0.88, respectively).Table 1Time period1993-20022003-20072008-2013Total no.103611021270MRDNo.186 (18%)182 (17%)143 (11%)Median age42.7yrs46.0yrs51yrs4-yr-OS (95%-CI)59% (53-67)66% (59-73)61% (53-72)4-yr-CIR (SE)21% (3%)25% (3%)29% (4%)4-yr-CID (SE)25% (3%)15% (3%)18% (3%)MUDNo.42 (4%)131 (12%)268 (21%)Median age41.1yrs47.9yrs50.6yrs4-yr-OS (95%-CI)52% (39-70)46% (38-58)54% (47-61)4-yr-CIR (SE)21% (3%)25% (3%)29% (4%)4-yr-CID (SE)25% (3%)15% (3%)18% (3%)Table 2ELN risk categorylowinter-1inter-2highTotal no.867711433318MRDNo.78 (9%)122 (17%)66 (15%)57 (18%)4-yr-OS (95%-CI)84% (76-93)50% (51-69)53% (41-67)57% (44-72)4-yr-CIR (SE)7% (3%)24% (4%)35% (6%)49% (7%)4-yr-CID (SE)13% (4%)23% (4%)23% (6%)12% (4%)MUDNo.21 (2%)139 (20%)76 (18%)109 (36%)4-yr-OS (95%-CI)69% (52-93)58 (49-68)52% (41 67)35% (26-46)4-yr-CIR (SE)0%28% (4%)32% (6%)44% (5%)4-yr-CID (SE)31% (11%)20% (4%)17% (5%)28% (4%)There were no differences in stratified survival analyses for time period between MRD and MUD-transplants in the low, intermediate-1 and intermediate-2 risk groups with respect to OS (p=0.12, p=0.86, p=0.98), CIR (p=0.28, p=0.54, p=0.94) and CID (p=0.09, p=0.57, p=0.39). In the high risk group, OS was significantly superior after MRD-transplant compared to MUD-transplant (p=0.02), but without significant differences in CIR (p=0.74) and CID (p=0.08). Equivalent efficacy could also be shown in a subgroup analyses focusing on all FLT3-ITD positive patients (MRD, n=103, MRD, n=147) for OS (p=0.71), CIR (p=0.53) and CID (p=0.69).Conclusions: Our results based on prospective interventional studies support the perception that MUD-transplants are equal to MRD-transplants in patients with AML in first CR. Only within the ELN high risk group, patients with MRD-transplants showed superior OS but without differences in CIR and CID as compared to MUD-transplants. DisclosuresKobbe:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Medac: Other; Astellas: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Neovii: Other. Götze:Celgene Corp, Novartis Pharma: Honoraria. Fiedler:TEVA: Travel reimbursement for meeting attendance Other. Petzer:Celgene: Honoraria, unrestricted grant Other. Lübbert:Cephalon / TEVA: Travel support Other. Greil:Bristol-Myers-Squibb: Consultancy, Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria; Astra-Zeneca: Honoraria; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Roche: Honoraria; Sanofi Aventis: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding. Döhner:Novartis: Research Funding. Döhner:TEVA: Research Funding.