Mitoxantrone and Etoposide with or without Intermediate-Dose Cytarabine for the Treatment of Patients with Primary Induction Failure or Relapsed Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2174-2174
Author(s):  
Steven Trifilio ◽  
Alfred Radamaker ◽  
Diane Newman ◽  
Kathryn Coyle ◽  
Katrin Carlson Leuer ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Prospective Trial ◽  
Response To Treatment ◽  
High Dose ◽  
Cell Transplant ◽  
Significant Difference ◽  
Primary Induction ◽  
Induction Failure ◽  
Acute Myeloid ◽  
Intermediate Dose

Abstract Abstract 2174 Introduction: The prognosis for patients with primary induction failure (PIF) or relapsed acute myeloid (Rel-AML) is poor. Mitoxantrone (M) plus etoposide (E)- based salvage regimens (ME), in particular, either alone or with intermediate dose cytarabine (MEC) are effective in these high risk patients; However, these regimens have not been directly compared. Heterogeneity in chemotherapy dose, dose escalation and age have been important limitations in the evaluation of previous studies. Also problematic, historically patients were classified according to FAB criteria. Since then, karyotype has been shown to be a main determinant of prognosis. The influence of karyotype on response to ME or MEC is currently unknown. Herein, we report the response to treatment with a fixed dosing schedule of ME or MEC in 66 patients treated for PIF or Rel-AML with intermediate(intermed-) or unfavorable(unfav-) risk cytogenetics. Differences in CR between ME and MEC subsets were analyzed to determine the effect of adding of C to ME. Methods: 66 consecutive patients with PIF or Rel-AML treated with either ME(n=37)or MEC(n=29) between 10/2004-12/2008 were evaluated. All patients had received initial induction therapy with daunorubicin 45–60mg/m2 IV bolus d1-3 and cytarabine 100mg/m2 CI d1-7(7+3), and consolidation with HIDAC if CR was achieved. ME and MEC were dosed according to previously published studies. The decision to use a given salvage was left to the discretion of the treating physician. Chi-Square test was used for statistical analysis. Results: Table1 shows there was no difference between the ME and MEC groups with regards to age, sex, % blasts at initial diagnosis, and %CR after initial induction with 7+3, or % patients who received inter- to high dose C prior to ME or MEC. Length of CR (after 7+ 3 and consolidation) was significantly longer in the MEC group. A significantly higher number of CR's was observed in the MEC group compared to ME(p=0.05). Within the MEC group, no difference in CR was observed between patients with intermed- and unfav-risk cytogenetics(p=0.96). The same was true within the ME group(p=0.13). When MEC was compared to ME, a significant difference in CR was observed in patients with unfav-risk cytogenetics(p=0.044) and patients <60years old. Prior to therapy, MEC patients had higher number of blasts. MEC patients had a significantly longer duration of remission. One patient in both the ME and MEC group died before hematopoetic reconstitution. Conclusion: In clinical practice, as observed in the present study, we observed a greater overall CR rate in patients who received MEC compared to those treated with ME, particularly in younger patients with unfav-risk cytogenetics. For those who achieved CR after MEC or ME, a longer duration of CR was observed in the MEC group compared to ME. These results could be particularly beneficial for those patients receiving salvage therapy as a temporizing measure prior to allogeneic hematopoetic stem cell transplant ion, and encourages confirmation from a prospective trial. Disclosures: No relevant conflicts of interest to declare.

Hematopoietic Cell Transplant Co-Morbidity Index (HCTCI) and Multiple Myeloma (MM) Survival After Autologous Hematopoietic Cell Transplantation (AHCT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4217-4217
Author(s):  
Anuj Mahindra ◽  
Ayman A Saad ◽  
Mei-Jie Zhang ◽  
Xiaobo Zhong ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Risk Groups ◽  
Hematopoietic Cell ◽  
High Dose ◽  
Cell Transplant ◽  
Co Morbidity ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 4217 Background: AHCT improves survival (OS) in newly diagnosed MM patients (pts) in large randomized trials. These trials have limited eligibility to younger, healthier pts. Selection of older pts and those with co-morbid illness for AHCT is problematic. HCT-CI, originally developed as predictor of post-allogeneic transplant outcomes, maybe valuable in stratifying risk of transplant related mortality (TRM) risk and OS in the AHCT setting. We investigated the relative impact of HCT CI along with other patient and MM related variables on outcomes after AHCT in a large cohort of transplant recipients. Methods: Outcomes of 1156 MM pts receiving AHCT after high dose Melphalan (MEL) between 2007 and 2010 reported to the CIBMTR (Center for International Blood and Marrow Transplant Research) were analyzed. HCTCI scores and individual comorbidities were prospectively reported at time of AHCT. Median follow up of survivors was 26 month. The impact of HCTCI and other potential prognostic factors including Karnofsky performance status (KPS) on OS were studied in multivariate Cox regression models. Results: HCTCI score was 0, 1, 2, 3, >3 in 42%, 18%, 13%, 13% and 14% respectively. Most common co-morbidities included pulmonary, diabetes, obesity, psychiatric, cardiac, renal and prior solid tumor. Using consolidated HCTCI scores, patients were stratified initially into 3 risk groups – HCTCI 0 (42%) vs. HCTCI 1–2 (32%) vs. HCTCI >2 (26%). Males and Caucasians were more likely to have greater HCTCI score. Higher HCTCI was associated with lower KPS <90 (33% in HCTCI 0 cohort vs. 50% in HCTCI >2). HCTCI score >2 was associated with MEL dose reduction to 140 mg/m2 (22% vs. 10% in score 0 cohort). Cytogenetic risk and MM related factors were not correlated with HCTCI. TRM at 12 month was 2%, 2%, and 3% for 3 risk groups. With extremely few TRM events, multivariate analysis did not suggest an impact of HCTCI. OS was 95%, 92%, 92% at 1 year and 87%, 81%, 80% at 2 year, respectively. OS was inferior for HCTCI >2 cohort (RR of death 1.48, p=0.02) and HCTCI cohort 1–2 (RR 1.37, p=0.04) compared with HCTCI 0 cohort. There was no significant difference in OS between HCTCI >2 vs. HCTCI 1–2 (p=0.64). Therefore the latter 2 groups were combined as the HCTCI >0 cohort [N=667] and compared with HCTCI=0 [N=489] in multivariate models. HCTCI >0 predicted inferior OS (RR of death= 1.41, p=0.01). Other significant predictors of inferior survival were KPS <90 (RR of death 1.61, p<0.01), IgA subtype (RR 1.64, p<0.01), >1 pretransplant regimen (RR 1.47, p<0.01), resistant MM at AHCT (RR 1.78, p<0.01). Major cause of death in both groups was progressive MM. Conclusion: In clinical practice, higher HCTCI score was associated with MEL dose reduction. Mortality after AHCT is predominantly related to MM progression/relapse with low incidence of TRM. Higher HCTCI scores were independently associated with inferior OS. KPS remains an important tool for risk stratification. Disclosures: No relevant conflicts of interest to declare.

Single Versus Tandem High Dose Therapy (HDT) Supported with Autologous Blood Stem Cell (ABSC) Transplantation Using Unselected or CD34-Enriched ABSC: Long-Term Results of a Two by Two Designed Randomized Trial in 225 Young Patients with Multiple Myeloma (MM). for the Group “Myelome-Autogreffe”, Caen, Creteil, Limoges, Paris, Strasbourg, France.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2320-2320 ◽  
Author(s):  
Jean-Paul Fermand ◽  
Kristell Desseaux ◽  
Jean Pierre Marolleau
Keyword(s):  
Randomized Trial ◽  
Disease Progression ◽  
Conflicts Of Interest ◽  
Autologous Blood ◽  
Prospective Trial ◽  
Early Death ◽  
Long Term Results ◽  
High Dose ◽  
Significant Difference

Abstract Abstract 2320 Poster Board II-297 In 1996, we initiated a multicenter prospective trial where patients aged under 56 with newly diagnosed symptomatic MM were randomly assigned up-front to receive either a single HDT (HDT1) or two sequential HDT (HDT2). In addition, all patients were independently randomized to be transplanted with unselected ABSC (unselected arm) or CD34-enriched ABSC (CD34 arm). We presented here updated data of this factorial 2*2 design trial, based on a median follow-up of 123 months.In all cases, patients first received one or 2 courses of high dose steroid containing regimens and ABSC were thereafter mobilized by cytoxan (CTX) (4 g/m2) and lenograstim (10 mg/kg/d). When appropriate (CD34 arm), part of collected ABSC were selected using the Isolex®300i system. The selection procedure resulted in a median purity of 95% (65-100) and in a more than two log tumor cell depletion. In the HDT1 arm, HDT was preceded by 3 monthly courses of a VAD-like regimen and combined a multi-drug regimen (carmustine, etoposide, melphalan 140 mg/m2 (MLP 140) and CTX 60 mg/kg) with a TBI (12 grays in 6 fractions). Patients treated in the HDT2 arm received MLP 140 alone (always supported by unselected ABSC) followed 2 to 3 months later by a second MLP 140 combined with etoposide (30 mg/kg) and 12-gray TBI. In both arms, TBI including HDT were supported with unselected or CD34 enriched ABSC. Two hundred and twenty-five patients were included in the study. Baseline characteristics of the four groups were close. All analyses were performed in intent to treat basis. In HDT groups, treatment completion rates were satisfactory, with 6/112 transplants not performed in the HDT1 group (allotransplant n=1, refusal n=1, mobilisation failure n=1, early death due to disease progression n=3) and 9/113 second transplant not performed in the HDT2 group (allotransplant n=2, mobilisation failure n=3, relapse post first transplant n=1, early death due to disease progression n=3). In the HDT1 and HDT2 groups, median time to TBI-including transplant was 4 months and 4.5 months, respectively.Present analysis did not show any significant difference in terms of early mortality, disease response and outcome of patients included in the two HDT groups. Early death rates (within 9 months post randomization, including toxic deaths and fatal progressive diseases) were 12% and 7% in the HDT1 and the HDT2 arms, respectively. At one year post-randomization, 32 (35 %) patients in the HDT1 and 32 (37 %) patients in the HDT2 groups were still in unmaintained CR or VGPR. The 2 OS curves were not statistically different (p= 0.60 by the log rank test), neither the EFS curves (p= 0.61). There was no significant interaction between selection CD34 and HDT in terms of outcomes. There was no evidence for benefit of CD34 selection as compared to the use of unselected ABSC. Of note, in the CD34 selected group, incidence of severe infections was increased. In conclusion, with a 10-years median follow-up, results of this randomized trial did not show any significant benefit of single HDT versus tandem HDT. Disclosures: No relevant conflicts of interest to declare.

Disease Knowledge In Chronic Myeloid Leukemia (CML) Patients as a Predictor of Compliance to Treatment.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4481-4481
Author(s):  
Courtney Nicole Johnson ◽  
Lisa Cowan ◽  
Gerry Lising Gorospe ◽  
Sikander Ailawadhi
Keyword(s):  
Patient Compliance ◽  
Conflicts Of Interest ◽  
Healthcare Providers ◽  
Treatment Compliance ◽  
Response To Treatment ◽  
Healthcare Personnel ◽  
Fisher Exact Test ◽  
Cell Transplant ◽  
Significant Difference ◽  
Compliance To Treatment

Abstract Abstract 4481 Background: Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL fusion protein have greatly improved outcome of patients with CML. Despite this, some patients fail to respond or lose their initial response on continued treatment. Reasons for this are not completely understood and may include poor patient compliance. We developed a questionnaire (CML-Q) to explore patient knowledge of CML and its predictive value in compliance and response to treatment. Relationship of compliance with serum drug levels was also studied. Methods: Patients enrolled in the CML program at LAC+USC Medical Center were eligible. CML-Q included 42 questions addressing patient demographics (14%), prior knowledge of CML (7%), specifics about cause and pathogenesis of CML (5%), self-perceived compliance (5%), satisfaction regarding treatment and healthcare providers (19%) and quality of life (50%). Physician assessed patient compliance was determined separately. In patients currently on imatinib, serum drug trough levels were determined using commercially available laboratory testing. T-test and Fisher Exact test were used for statistical analysis with a 0.05 nominal significance level. Results: The CML-Q was administered to 80 patients. Of these, 39 responded while the rest either declined or were lost to follow up. Amongst the 39 evaluable patients (18 females; 46%, 21 males; 55%) median age was 47.5 yr (range 25–78) and median time since diagnosis was 34.1 mth (range 9–230). Majority of these (n=33; 84.6%) were on TKIs at the time of analysis. Four (11%) patients had received previous stem cell transplant for CML. Amongst the patients 19 (49%) were on first, 7 (18%) on second, 5 (13%) on third, 5 (13%) on fourth, 2 (5%) on fifth and 1 (2%) on seventh line treatment. Twenty-six patients (66%) responded to the Spanish version of CML-Q, while 13 (34%) responded in English. Responses to CML-Q were complete in 49% cases, while others had some skipped or erroneous responses. In such cases, the skipped or erroneous answers were withdrawn from final analysis while questions with complete and unambiguous responses were included. Patient compliance was classified as patient-perceived or physician-perceived. A kappa statistic between these two groups was 0.13, suggesting only slight agreement between the patient's own and the physician's assessment of compliance to treatment. Thus, for compliance-related analysis, patients were divided into true-compliant (TC) (patient-perceived and physician-perceived compliant) (42%) and non-compliant (NC) (reported non-compliant by the patient or physician or both) (58%) groups. There was a significant difference between TC and NC responses to the CML-Q regarding time since CML diagnosis (< or >3 yr, respectively) (p=0.04), specific questions addressing compliance to medications (p=0.002) and those addressing treatment staff's explanation of the effects of treatment (p=0.01). In a subset of patients taking imatinib (n=20; TC=10, NC=10), serum trough imatinib levels were evaluated. There was no statistically significant difference between the mean serum imatinib trough level of TC (1448 ng/ml) and NC (1321 ng/ml) groups (p=0.99). Response to treatment for all patients was classified as optimal or suboptimal based on established CML response milestones. In the TC group 94% patients had optimal responses while 76% patients had optimal responses within the NC group. This was not statistically significant (p=0.19). Conclusions: There is limited data on factors that may affect treatment compliance in CML patients, and ultimately may dictate efficacy of therapeutic interventions. Using an extensive CML questionnaire, we observed that compliance may be perceived differently by patients and healthcare providers. Specific questions regarding treatment adherence were able to differentiate TC and NC groups. Patients were more likely to comply if they were aware of the treatment effects, as explained by healthcare personnel. There was no significant association between compliance and serum imatinib levels. NC patients were more likely to have a CML diagnosis for >3 yrs, suggesting that patient education should be reinforced with continued treatment. Although not statistically significant, compliant patients more often had optimal response to treatment. Our results suggest that patient compliance to treatment in CML should be further evaluated in larger cohorts prospectively. Disclosures: No relevant conflicts of interest to declare.

A Phase 1 Study of Total Marrow Irradiation Combined with High-Dose Melphalan for Patients with Relapsed/ Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4646-4646
Author(s):  
Pritesh R. Patel ◽  
Annie L. Oh ◽  
Matthew Koshy ◽  
Bulent Aydogan ◽  
Karen Sweiss ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Phase 1 ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Significant Difference ◽  
Total Marrow Irradiation ◽  
High Dose Melphalan

Abstract High dose melphalan at 200mg/m2(Mel200) followed by autologous stem cell transplant (ASCT) prolongs the survival of patients with multiple myeloma (MM) although it does not prevent relapse. Enhancing the anti-myeloma effect of pre-transplant conditioning without increasing toxicity is an important goal. To this purpose, intensity modulated radiation therapy (IMRT) can be used to deliver radiation to the marrow (total marrow irradiation, TMI) while sparing other organs. Here we tested the safety of combining linear accelerator based TMI to Mel200 in a phase 1, 3+3 trial. Twelve patients with MM who relapsed after at least one line of therapy were enrolled in 3 dose cohorts (3Gy, 6Gy and 9Gy). Prior ASCT was permitted. All patients received Mel200 over 2 days. In addition, 1.5Gy TMI was administered twice daily for 1, 2 or 3 days depending on dose cohort. Dose-limiting toxicity was defined as the occurrence of any NCI-CTCAE grade 4/5 non-hematologic toxicity or failure to engraft prior to day 30 after ASCT. Quality of life (QoL) was assessed using the FACT-BMT scale at baseline and 90-100 days after ASCT. Three groups of patients were enrolled and received 3Gy (n=3), 6Gy (n=3) or 9Gy (n=6). Median age at time of transplant was 66 years (range 40-71). Three patients had high risk FISH/ karyotype as defined by IMWG criteria. Median lines of prior therapy was 2 (range 1-4). Five patients (42%) had undergone prior autologous transplant. Of eleven patients (92%) who received prior lenalidomide, 7 (58%) were considered lenalidomide refractory. Similarly, of 11 (92%) patients previously treated with bortezomib, 6 (50%) were considered refractory. Eleven patients had a pre-transplant PET scan performed with 8 (73%) having skeletal PET avidity. All patients received TMI as scheduled. The mean reduction in dose to organs at risk (lens, oral cavity, kidneys, liver, bowels, lung) ranged from 25-63%. Median time to neutrophil (greater than 0.5x109/L) and platelet (greater than 20x109/L) engraftment were 10 (range 9-15) and 13 (range 9-17) days respectively. There were no dose limiting toxicities. Five patients experienced a total of 7 NCI CTCAE grade 3 toxicities including: diarrhea, n=2; mucositis, n=3; and nausea, n=2. Four of 6 patients who received 9Gy did not experience any toxicity greater than grade 2. Using the FACT-BMT scale, we observed that there was no significant difference in QoL between baseline and day 90 assessments. At day 100 overall response rate was 82% with 5 patients (45%) achieving a complete response. Four of 6 patients in the 9Gy cohort achieved at least a very good partial response. With a median follow up of 314 days, all patients were alive and only 4 patients (33%) relapsed. In this phase 1 trial we showed that TMI at 9Gy can be safely added to Mel200 without an increase in transplant related toxicities. Initial promising clinical results, even in high risk MM patients, will be further tested in a phase 2 study. Disclosures No relevant conflicts of interest to declare.

Initial Remission Duration Is the Most Important Predictor of Outcome Following FLAG-Amsacrine Salvage of AML in First Relapse,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3631-3631
Author(s):  
Chun Yew Fong ◽  
George Grigoriadis ◽  
Jay Hocking ◽  
Philip Campbell ◽  
Anthony P. Schwarer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Time ◽  
Conflicts Of Interest ◽  
High Dose ◽  
Cell Transplant ◽  
Platelet Recovery ◽  
Free Interval ◽  
Remission Duration ◽  
Significant Difference ◽  
First Relapse

Abstract Abstract 3631 Introduction: Despite improvements in clinical outcome with intensification of induction and consolidation chemotherapy, the majority of patients with AML will ultimately relapse. At first relapse, the European Prognostic Index (EPI) stratifies outcome according to relapse-free interval, karyotype, age and prior allogeneic stem cell transplant (Breems et al, JCO 2005; 1969). Recently, FLT3-ITD has also emerged as a predictor of poor outcome in relapsed patients (Chevallier et al, Leukemia 2011; 939). The purpose of this study was to define predictors of outcome in patients with AML treated at first relapse with FLAG-Amsacrine (Fludarabine 30mg/m2/day days 1–5; Cytarabine 2g/m2/day days 1–5; G-CSF 300mcg/day days 1–6; Amsacrine 100mg/m2/day days 1–3), particularly in the context of FLT3-ITD status and prior high-dose ara-C (HiDAC) exposure. Methods: Patients treated at The Alfred, Box Hill, and Geelong hospitals with FLAG-Amsacrine between 2002 and 2011 were retrospectively identified. Statistical analysis of clinical outcomes related to toxicity, response and survival was performed with SPSS™ and GraphPad Prism™. Results: 56 patients with AML in first relapse (28 male, 28 female), median age 50.5 years (range 18–70), received FLAG-Amsacrine as salvage therapy. The patient characteristics are summarised in Table 1. 48 patients had a history of prior HiDAC-exposure and 11 (19.7%) were known to be FLT3-ITD positive. The median time to neutrophil and platelet recovery in those attaining CR was 28.5 and 32 days respectively. 42-day treatment related mortality was 12.5%. The overall CR/CRi rate after FLAG-Amsacrine was 61% with 27% refractory to treatment. Median EFS (censored at the time of subsequent allograft) and OS from treatment commencement was 6.7 and 10.6 months respectively (median follow up 6.5 months; range 1–55 months). As most patients with AML receive HiDAC at some stage during induction or consolidation, analysis of outcomes according to the EPI score in those with prior HiDAC exposure was performed. A statistically significant difference in OS was not observed between intermediate and poor risk EPI groups (41 vs 42% 1yr OS respectively; p=0.74) (Figure 1). An analysis of each EPI risk determinant showed that a relapse-free interval (RFI) of less than 6 months was the most important factor influencing overall survival (4 vs 17 months, p=0.03). In patients with early relapse (RFI <6 months) treated with FLAG-Amsacrine, survival was dismal, even in those not previously exposed to HiDAC (Figure 2). Adverse risk karyotype (p=0.22), prior allograft (p=0.92) and age >60 (p=0.91) did not negatively impact on OS after FLAG-Amsacrine. There was no significant difference in the CR/CRi rate (60 vs 62.5%, p=1.0), EFS (p=0.33) or OS (p=0.81) of patients who had received FLAG-Amsacrine following prior HiDAC based therapy compared with those who had not received HiDAC. A significant difference in OS was not observed in relation to FLT3-ITD status (p=0.86; Figure 3). 22 patients went on to allogeneic stem cell transplantation with a median time to allograft of 83.5 days (range 29–340 days). Patients who received an allograft had longer median OS (not reached vs 4 months, p=0.01). 16 patients remain in continuous CR, with a median remission duration of 13 months (range 3–45 months). Conclusion: FLAG-Amsacrine is a tolerable and effective salvage regimen for AML in first relapse and represents an effective bridge to transplantation. Alternative investigational approaches should be considered for patients with very short duration of first remission, where outcomes after FLAG-Amsacrine were poor, even in the absence of prior HiDAC-based therapy. Disclosures: No relevant conflicts of interest to declare.

A Comparative Retrospective Survey of Reinduction Chemotherapy Regimens for Acute Myeloid Leukemia (AML) in First Relapse: A Single-Institution Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4273-4273 ◽  
Author(s):  
Andrew Brunner ◽  
Hossein Sadrzadeh ◽  
Lillian Werner ◽  
Karen K. Ballen ◽  
Yi-Bin A. Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Laboratory Data ◽  
Categorical Variables ◽  
High Dose ◽  
Single Institution ◽  
Significant Difference ◽  
First Relapse ◽  
Acute Myeloid

Abstract Abstract 4273 Introduction: Relapsed acute myeloid leukemia (AML) carries a poor prognosis. Although most newly diagnosed patients with AML achieve a complete remission after initial induction (CR1) using standard chemotherapy regimens, relapse follows in the majority of cases. The optimal reinduction chemotherapy regimen for patients following relapse remains unknown, and there is little comparative data to guide selection between various available reinduction regimens. The current study is a single-institution retrospective review over a 10 year period, which seeks to compare rates of response, disease-free survival (DFS) and overall survival (OS) between different reinduction regimens among patients with AML in first relapse. Methods: We performed a retrospective chart review of patients with AML who relapsed following CR1, and who were treated with reinduction chemotherapy at our institution between January 1, 2000, and December 31, 2010. Our patients were categorized into four groups based upon the type of reinduction chemotherapy they received: MEC (mitoxantrone, etoposide, cytarabine) or similar etoposide-containing regimens, 7+3 (infusional cytarabine and anthracycline) or 7+3-based regimens, HiDAC (high-dose cytarabine)-based regimens, and “other” combinations (less frequently used regimens including cytarabine and topotecan; decitabine; gemtuzumab; mitoxantrone and etoposide). Patients were identified using medical billing diagnosis codes, and included if they were above age 18 at diagnosis, obtained CR1 but experienced subsequent relapse, and were treated during first relapse with reinduction with intent to achieve remission. Exclusion criteria included patients with acute promyelocytic leukemia, primary refractory disease, and patients who were given chemotherapy for persistent disease on a mid-treatment bone marrow biopsy. Information about date of diagnosis, treatment regimens, tumor cytopathology and histology, comorbidities at diagnosis, and presenting laboratory data were collected. Statistical analysis was performed using the Kaplan-Meier method, and log rank tests where appropriate, to analyze DFS and OS. Fisher’s exact test was used to assess the associations between categorical variables. Results: We identified 66 patients who were treated with reinduction chemotherapy for AML in first relapse; of these, 28 (42%) achieved CR2. The type of reinduction chemotherapy received was not associated with any difference in the rates of CR2 (p=0.19). Patients who achieved CR2 had a median DFS of 5.1 months. For all patients, including those who failed to achieve CR2, the median OS following reinduction was 4.9 months. There was no significant difference in OS between re-induction regimens (p=0.09). However, there was a statistically significant difference in median DFS depending on regimen (p=0.006). Patients who received 7+3-based regimens, and to a lesser degree MEC, had longer median DFS than HiDAC-based regimens (8.9, 3.4, and 2.0 months, respectively). Patients who received 7+3-based re-induction regimens had a longer duration of preceding CR1 (p=0.006). Longer duration of CR1 (≥7.4 months, the median in our data) was associated with higher rate of CR2 (61% vs 22%, p=0.03) and OS (8.9 vs 2.9 months, p=0.0006) compared to duration of CR1 <7.4 months. Patients who were given “other” regimens (including demethylating therapies) were on average older (62 years old compared to 50, 52, and 54 years old in other groups); however, they had CR2 rates and OS similar to patients receiving 7+3, MEC, or HiDAC-based regimens. Conclusion: According to this retrospective analysis, patients treated with MEC or 7+3-based reinduction chemotherapy regimens had improved DFS compared to patients given HiDAC-based regimens. However, as expected, patients treated with 7+3-based reinduction chemotherapy were also more likely to have experienced a longer duration of CR1. Longer CR1 (≥7.4 months) was associated with improved DFS and OS following reinduction chemotherapy. It remains unclear whether the improved DFS seen in those AML patients who received 7+3-based regimens is due to the type of chemotherapy, or if this is related to the characteristics of their underlying disease, as manifested by the longer duration of CR1 seen in this treatment group. Our data does suggest that MEC may be preferable to HiDAC-based regimens for patients with early relapse following CR1. Disclosures: No relevant conflicts of interest to declare.

Rapid and Sustained Engraftment of a Single Allogeneic Ex-Vivo Expanded Cord Blood Unit (CBU) After Reduced Intensity Conditioning (RIC) in Adults. Preliminary Results of a Prospective Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 486-486 ◽  
Author(s):  
Noel Milpied ◽  
Bernard Dazey ◽  
Zoran Ivanovic ◽  
Pascale Duchez ◽  
Stephane Vigouroux ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Prospective Trial ◽  
Allogeneic Transplantation ◽  
Ex Vivo Expansion ◽  
High Dose ◽  
Cell Transplant ◽  
Inform Consent ◽  
Cd34 Cells ◽  
D 12

Abstract Abstract 486 CBU is a widely used source of stem cells for allogeneic transplantation (SCT). Engraftment rate and speed of a single CBU in adults remains unsatisfactory. Transplantation of 2 CBU may overcome this problem to the expense of an increased incidence of GVHD. Until now, attempts at using ex-vivo expanded CBU have been unsuccessful to promote long term engraftment of the expanded product. We report the results achieved in the first 8 Pts included in a PCT of transplantation of a single ex-vivo expanded allogeneic CBU. Eudract 2008–006665–81, Clinicaltrials.gov NCT 01034449. Methods: Adults patients with an indication for SCT and unable to tolerate MAC (age>45, comorbidities, previous high-dose therapy) were included after inform consent if no Id sibling, no MUD 9 (C or DQ mismatch accepted) to 10/10 HLA matches and no CBU fulfilling the HLA matching (≥ 4/6) and richness (≥ 3 to 4 × 107 TNC/kg before thawing) criteria were available. RIC consisted of Flu (40 mg/m2/d × 5d), Cyclophosphamide (50 mg/kg × 1d) ICT 2 Gy. GVHD prevention consisted of MMF (d-3 to d28) and CSA from d-3. Graft engineering: 1 CBU with > 2 TNC/kg < 3 and 4 to 6 HLA compatibilities was thawed, CD34+ cells were selected through magnetic device (Miltenyi) and submitted to ex-vivo expansion in SF medium ( HPO1-Macopharma) supplemented with SCF, Flt3l, G-CSF and TPO during 12 days, starting d-12 of the transplantation (Ivanovic, Cell Transplant 2011) CD34 neg cells were cryopreserved. On d0, expanded cells were washed and resuspended in HSA 4% and upon viability and sterility were injected to the pt. Cd34 neg cells were thawed and injected to the pt 3 h later. Results: From 03/2010 to 06./2011 8 pts have been included, med age 55y.o. (26–64) with AL: 3, Hodgkin's: 2, MDS: 3. Pts had received 1 to 3 lines of Tx (med:2). For 1 pt the expanded product was contaminated and this pt then received a back-up unmanipulated CBU. He engrafted correctly and is AW at 14 m with full donor chimerism. For the 7 other pts, the ex-vivo median fold expansion of CD34+ cells and TNC was 39 (29–75) and 390 (127–526) respectively, leading to a graft that contained 1.3 to 13 × 106 CD34+ cells/kg (med: 2 × 106/kg). The CD34 neg counterpart contained 3 × 106 CD3+/kg (1–5) and 0,9 × 106 CD19+ cells/kg (0,3–1,5). At d42, 6/7 pts who received the expanded graft engrafted with ≥99% donors cells. A 2d RIC was performed followed by a double CBU transplant in the patient who did not engraft. That 2d graft again failed to engraft. However the patient remains alive at 9m. For the 6 pts who engrafted with the expanded product the time to reach 500, 1000 PMN's and 20 000 plts/mm3 was 7d (6–19), 8d (6–21) and 24d (0–39) respectively. The chimerism on WBC and CD3+cells (evaluated on d 15, 42, 60, 100, 180, 365) remains full donor up to 1 year + after transplant (1y+: 2 pts; 6m+: 1pt; 180d+: 1 pt; 60d+: 1pt) or to relapse (at 1y) in the one pt who relapsed. Five pts experienced an AGVHd (grade III-IV: 1 pt). With a median FU of 10m (2 to 18m) 7 pts are alive, 6 wo disease. One pt died 1y after transplant from relapse. Conclusion: Ex-vivo expansion of a single CBU is feasible and reproducible. Transplantation of the expanded product together with the CD34 neg counterpart of the same CBU produces rapid, complete and sustained donor engraftment after RIC in adults. Disclosures: No relevant conflicts of interest to declare.

High-Dose Cyclophosphamide In Combination With G-CSF Versus G-CSF Alone For Mobilization Of Hematopoietic Stem Cells After Induction Therapy Including Velcade, Cyclophosphamide and Dexacort

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5369-5369
Author(s):  
Noam Benyamini ◽  
Irit Avivi ◽  
Eldad J Dann ◽  
Tsila Zuckerman ◽  
Lavi Noa ◽  
...  
Keyword(s):  
Stem Cell ◽  
Induction Therapy ◽  
Conflicts Of Interest ◽  
Young Patients ◽  
High Dose ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Significant Difference ◽  
The Difference

Abstract Introduction Even in the era of novel agents, high-dose chemotherapy followed by autologous stem cell transplant (ASCT) is considered to be an essential part of treatment for young patients with multiple myeloma (MM), providing durable responses. Currently, VCD (velcade, cyclophosphamide and dexacort) is one of the most commonly employed induction regimens. High-dose cyclophosphamide (HDC), often used in stem cell (SC) mobilization in conjunction with G-CSF, is associated with adverse events and only modest efficacy against myeloma. An alternative mobilization regimen, using G-SCF alone, has been recently suggested to provide adequate SC collection with less toxicity. Nevertheless, the efficacy and safety of using G-SCF alone after VCD induction have not been fully explored. The current study compares the safety and efficacy of mobilization using HDC-G-CSF versus G-CSF alone in MM patients treated with VCD as induction therapy. Methods The study was approved by the Institutional Review Board of the Rambam Medical Center (Approval # 0110-13 RMB). Data on all consecutive newly diagnosed transplant-eligible MM patients, treated with VCD between 2009 and 2012, were retrospectively reviewed. Eligibility criteria were: VCD induction followed by SC mobilization, either with G-CSF or HDC-G-CSF, with subsequent high-dose melphalan (200 mg/m2) and ASCT. The mobilization protocol was chosen at the discretion of the treating physician. Evaluated data included patient characteristics, SC collection and engraftment related parameters. For statistical analysis, Mann-Whitney non-parametric test for 2 independent groups was used. Results 79 patients were included: 50 mobilized with HDC-G-CSF, and 29 with G-CSF alone. There were no statistically significant differences in terms of patient demographic and MM-related characteristics (MM type, ISS, number of VCD cycles, and disease status at the end of induction) between the 2 cohorts. The first day of SC collection yielded a median of 14.6x106 (range 1.9 -10.1) vs 5.3x106 CD34 cells/Kg (range 0.6-37.7) in the HDC-G-CSF vs the G-CSF groups (p=<0.001). A significantly higher total CD34 collection was obtained in the HDC-G-CSF treated patients (15.9 x 106 vs 8.1x106 CD34 cells/Kg, respectively, P<0.001). Additionally, a bivariate analysis showed that male gender and platelet count (>150,000/mL) prior to mobilization had a significant impact on the outcome of SC collection. The percentage of patients needing more than one day of leukopheresis following HDC-G-CSF and G-CSF was 42% and 83%, respectively. During treatment and mobilization, 20% of patients in the HDC-G-CSF cohort were hospitalized due to neutropenic fever, while none of the patients from the G-CSF group required hospitalization (P<0.011). In all patients apart from one (G-CSF group), at least the minimum of CD34 cells/Kg required to perform a transplant (2x106 CD34 cells/Kg) was collected. Moreover, most patients succeeded in collecting >5x106 CD34 cells/Kg (96% and 93.1% in HDC-G-CSF and G-CSF groups, respectively). Notably, the difference between the groups achieved statistical significance only in collection of >8x106 CD34 cells/Kg (88% and 55.2% of patients treated with HDC-G-CSF and G-CSF, respectively). The median amount of cells administered at transplantation was 7.9x106 and 4.9x106 for patients mobilized with HDC-G-CSF vs G-CSF, respectively, reflecting the difference in the total amount of collected cells. Despite the variation in the amount of transplanted cells, no significant difference in parameters of the transplant outcome was revealed between the 2 cohorts:  time to neutrophil engraftment (>500 cells/µl) at a median of 12 days in both groups and platelets engraftment (>25,000 cells/µl) at a median of 14.5 vs 13 days in the HDC-G-CSF and G-CSF groups, respectively. The length of hospitalization, approaching 17 days, did not differ between the 2 groups. Conclusions Mobilization using HDC-G-CSF results in a higher total amount of collected CD34 cells and requires less days of leukophersis. Nevertheless, G-CSF alone provides a sufficient number of SC for transplantation in almost all patients, and this approach is much safer than treatment with HDC-G-CSF. Since engraftment results are identical with the 2 mobilization methods, the use of G-CSF alone could be considered as a preferable cell mobilization protocol in patients previously exposed to VCD induction. Disclosures: No relevant conflicts of interest to declare.

Mitoxantrone and etoposide with or without intermediate dose cytarabine for the treatment of primary induction failure or relapsed acute myeloid leukemia

2012 ◽  
Vol 36 (4) ◽  
pp. 394-396 ◽  
Author(s):  
Steven M. Trifilio ◽  
Alfred W. Rademaker ◽  
Diane Newman ◽  
Katherine Coyle ◽  
Katrin Carlson-Leuer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Primary Induction ◽  
Induction Failure ◽  
Relapsed Acute Myeloid Leukemia ◽  
Acute Myeloid ◽  
Intermediate Dose

scholarly journals NUP-98 Rearrangements Led to the Identification of Candidate Biomarkers for Primary Induction Failure in Pediatric Acute Myeloid Leukemia

2021 ◽  
Vol 22 (9) ◽  
pp. 4575
Author(s):  
Vincenza Barresi ◽  
Virginia Di Bella ◽  
Nellina Andriano ◽  
Anna Provvidenza Privitera ◽  
Paola Bonaccorso ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mutational Analysis ◽  
Integrated Analysis ◽  
Induction Phase ◽  
Pediatric Acute Myeloid Leukemia ◽  
Expression Arrays ◽  
Primary Induction ◽  
Induction Failure ◽  
Acute Myeloid

Conventional chemotherapy for acute myeloid leukemia regimens generally encompass an intensive induction phase, in order to achieve a morphological remission in terms of bone marrow blasts (<5%). The majority of cases are classified as Primary Induction Response (PIR); unfortunately, 15% of children do not achieve remission and are defined Primary Induction Failure (PIF). This study aims to characterize the gene expression profile of PIF in children with Acute Myeloid Leukemia (AML), in order to detect molecular pathways dysfunctions and identify potential biomarkers. Given that NUP98-rearrangements are enriched in PIF-AML patients, we investigated the association of NUP98-driven genes in primary chemoresistance. Therefore, 85 expression arrays, deposited on GEO database, and 358 RNAseq AML samples, from TARGET program, were analyzed for “Differentially Expressed Genes” (DEGs) between NUP98+ and NUP98-, identifying 110 highly confident NUP98/PIF-associated DEGs. We confirmed, by qRT-PCR, the overexpression of nine DEGs, selected on the bases of the diagnostic accuracy, in a local cohort of PIF patients: SPINK2, TMA7, SPCS2, CDCP1, CAPZA1, FGFR1OP2, MAN1A2, NT5C3A and SRP54. In conclusion, the integrated analysis of NUP98 mutational analysis and transcriptome profiles allowed the identification of novel putative biomarkers for the prediction of PIF in AML.

Sign in / Sign up

Export Citation Format

Share Document