Influence of NPM1 and FLT3-ITD Status On Outcome in Relapsed/Refractory AML Patients with Normal Karyotype and Receiving Salvage Therapy Including Gemtuzumab Ozogamicin (GO).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3110-3110
Author(s):  
Patrice Chevallier ◽  
Thomas Prebet ◽  
Arnaud Pigneux ◽  
Mathilde Hunault ◽  
Jacques Delaunay ◽  
...  
Keyword(s):  
Salvage Therapy ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Gemtuzumab Ozogamicin ◽  
Chemotherapeutic Agents ◽  
Cell Transplant ◽  
Salvage Regimen ◽  
Leukemia Diagnosis ◽  
Major Interest ◽  
Refractory Aml

Abstract Abstract 3110 Poster Board III-47 The aim of this study was to investigate the influence of the NPM1/FLT3-ITD status on outcome in relapsed/refractory AML patients with normal karyotype who received a salvage regimen using GO as monotherapy or in combination with other agents. For this purpose, we analyzed the outcome of 57 AML patients with normal karyotype treated between 2001 and 2009. Patients received GO as monotherapy or in combination with other chemotherapeutic agents at time of relapse (n=36) or in the setting of refractory disease (n=21). There were 26 males and 31 females with a median age of 52 (range, 20-70) years at time of leukemia diagnosis. The FAB distribution included 2, 13, 15, 11, 12 and 1 AML cases from the M0, M1, M2, M4, M5 and M6 subgroups, respectively. Three cases were considered as unclassified. In addition, 5 patients had secondary AML. All patients were CD33 positive with a median CD33 expression level of 98%. As salvage treatment, 46 patients received the MIDAM regimen (GO: 9 mg/m2 at day 4 + Cytarabine 1g/m2/12 hours day 1-5 + Mitoxantrone 12 mg/m2/day day 1-3).3 In 2 patients receiving the MIDAM regimen, Mitoxantrone was omitted to avoid cardiac toxicity. Four patients received GO as monotherapy at 9 mg/m2 (n=3) or at 6 mg/m2 (n=1). The 5 remaining patients received GO 3 to 9 mg/m2 combined with other chemotherapeutic agents (Cytarabine + VP16 + GO, n=2; Cytarabine + Idarubicine + GO, n=2; Cytarabine + Amsacrine + GO, n=1). After salvage therapy, 25 patients could proceed and receive consolidation with an allogeneic stem cell transplant. In this series, all patients could be screened in the blood or bone marrow for mutations in the NPM1 and in the FLT3 gene (ITD mutations) at diagnosis. Numbers of patients according to NPM1/FLT3-ITD status were as follow: (+/−): n=14, (+/+): n=9, (−/−): n=19, (−/+): n=15. The same proportion of refractory patients was observed in the favourable NPM1+/FLT3-ITD- sub-group as compared to the other sub-groups (36%, n=5/14 vs 37%, n=16/43). With a median follow-up of 23.3 (range, 2.3-94.5) months for surviving patients, OS was 46.5% (95%CI, 33.6-59.9%) at 2 years. CR, relapse and death rates according to NPM1/FLT3-ITD status were as follow: CR: (+/−): 85%, (+/+): 66%, (−/−): 47%, (−/+): 73%, P=NS; Relapses: (+/−): 33%, (+/+): 33%, (−/−): 33%, (−/+): 54%, P=NS; Deaths: (+/−): 28%, (+/+): 78%, (−/−): 58%, (−/+): 66%, P=0.02 Also, the death rate was significantly lower in FLT3-ITD- patients as compared to FLT3-ITD+ cases (45% vs. 71%, P=0.05). OS was significantly higher in the NPM1+/FLT3-ITD- sub-group as compared to other patients (78% vs. 36% at 2 years, P=0.026). In conclusion, and although this needs to be confirmed in a prospective setting, refractory/relapsed AML patients combining a normal karyotype and a NPM1+/FLT3-ITD- molecular status are likely to remain in a “favorable prognosis” category when receiving salvage therapy. Such information is of major interest for patients counselling and for the design of salvage therapy approaches. Disclosures No relevant conflicts of interest to declare.

A Phase II Study of Velcade (V), Doxil (D) in Combination with Low-Dose Thalidomide (T) as Salvage Therapy for Patients (pts) with Relapsed (rel) or Refractory (ref) Multiple Myeloma (MM) and Waldenstorm Macroglobulinemia (WM): Encouraging Preliminary Results.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2421-2421 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Kena C. Miller ◽  
Philip McCarthy ◽  
Laurie A. DiMiceli ◽  
Jihnee Yu ◽  
...  
Keyword(s):  
Phase Ii ◽  
Salvage Therapy ◽  
Low Dose ◽  
Treatment Options ◽  
Hematologic Malignancies ◽  
Cell Transplant ◽  
Synergistic Activity ◽  
Salvage Regimen ◽  
Highly Active ◽  
Development Of Resistance

Abstract In MM, tumor microenvironment (ME) plays an important role in disease progression, dissemination, and development of resistance to therapy. Pts with rel/ref MM have limited treatment options. Therefore, targeting the ME simultaneously with malignant cells may be an effective way to overcome resistance in pts with rel/ref MM. Orlowski et al recently reported synergistic activity of V+D in patients with hematologic malignancies. A phase II trial initiated at our institute is exploring this approach, targeting the MM cell as well as its ME, using a combination of Velcade (V), Doxil (D) and low-dose thalidomide (T) as salvage therapy for pts with rel/ref MM. Pts with rel/ref disease are eligible for this study. V is given at 1.3mg/m2 (D1,4,15,18) and D at 20mg/m2 (D1,15) every 4 weeks with daily T (200 mg) for 4–6 cycles. SWOG criterion was used to evaluate response. Low-dose coumadin (1–2 mg po qd) was used for prevention of venous thromboembolism (VTE). Eighteen pts (7M, 11F; median age 56, range 44–80 yrs; 16MM, 2 WM) have been enrolled to date. All pts had Stage III disease, median b2M of 4.8 (nl range: 0–2.15) and median prior therapies 2 (range 1–7). Prior therapies included stem cell transplant in (46%), T (54%), adriamycin(A) (70%) and steroids (92%). Thirteen pts have completed at least 1 cyc and are available for toxicity and response evaluation. One pt died of sepsis prior to completing 1 cyc and 1 pt with PR was taken of study for non-compliance after 1 cyc. ORR was 100% (13/13) with 5PR and 8MR. All pts are currently continued on therapy. Toxicity: 2 pts developed Gr. II plantar-palmar erythrodysthesia (PPE) and 1 had Gr. III cellulitis. No VTE was noted. VDT is a highly active salvage regimen in pts with rel/refr MM. Responses were noted despite prior failure of steroids, T or A. It is well tolerated without any significant non-hematologic Gr. III/IV toxicity. VTE does not appear to be a problem. Updated results of this first cohort of pts will be presented at the annual ASH meeting.

All-Trans Retinoic Acid and Gemtuzumab Ozogamicin as Adjunct To Salvage Therapy in Primary Refractory Acute Myeloid Leukemia: Results of Consecutive Phase II Studies of the AMLSG.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1949-1949
Author(s):  
Richard F. Schlenk ◽  
Konstanze Dohner ◽  
Martina Kerz ◽  
Francisco del Valle ◽  
Björn Heydrich ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Salvage Therapy ◽  
Odds Ratio ◽  
Gemtuzumab Ozogamicin ◽  
Prognostic Impact ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Significant Difference ◽  
The Impact ◽  
Refractory Aml

Abstract Background: In primary refractory patients the achievement of a response to salvage therapy is of enormous prognostic impact. Aims: To evaluate the impact of all-trans retinoic acid (ATRA) and gemtuzumab ozogamicin (GO) given as adjunct to high-dose cytarabine based intensive salvage therapy in primary refractory younger patients on clinical outcome. Methods: Between 1993 and 2006 264 consecutive patients (median age: 48 yrs) were evaluated. All patients had primary refractory AML after one cycle of ICE (idarubicine, cytarabine, etoposide). The different salvage therapies were as follows: from 1993–1998: S-HAM for patients <55 years of age [cytarabine 3g/m2 bid. days 1,2,8,9, mitoxantrone 10mg/m2 days 3,4,10,11] and HAM for patients >=55 years of age [cytarabine 3g/m2 bid., days 1–3, mitoxantrone 12mg/m2 days 2,3]; from 1998 to 2004 A-HAM [HAM with ATRA 45mg/m2 days 3–5, 15mg/m2 days 6–28]; from 2004 up to date: GO-A-HAM [A-HAM with gemtuzumab ozogamicin 3g/m2 day 1]. Results: The distribution of the different salvage therapies was HAM n=21, S-HAM n=22, A-HAM n=118, GO-A-HAM n=62, other n=31, or no further therapy n=10. CR-rate according to salvage therapy was GO-A-HAM 49%, A-HAM 34% S-HAM 23%, HAM 14%. Treatment related mortality did not differ between regimens. No CTC-grade 3–5 liver toxicity was seen in patients receiving GO-A-HAM. Logistic regression on the achievement of CR revealed that regimens containing ATRA (odds ratio 2.0, p=0.05) and GO (odds ratio 1.9 p=0.05) were associated with response. 151 of 264 patients have received a stem cell transplantation as consolidation therapy (n=59 MRD, n=79 MUD, n=6 haplo-identical donor, n=7 autologous). The rates of severe veno occlusive disease after transplant was identical (5%) for patients receiving a salvage therapy including GO and those who did not. Survival analysis revealed a significant difference (p= 0.00178) with a median survival of 16.2 months for GO+ATRA, 12.5 months for ATRA versus 7.2 months for the others. Conclusions: Although retrospective in nature our study suggests that ATRA and GO as adjunct to salvage therapy improves CR rates and survival in primary refractory AML patients.

Gemtuzumab Ozogamicin (GO) in Infants with Acute Myeloid Leukemia (AML) – Combined Results from the Children’s Oncology Group (COG) Trials, AAML03P1 and AAML0531

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 377-377
Author(s):  
Erin M. Guest ◽  
Richard Aplenc ◽  
Lillian Sung ◽  
Susana C. Raimondi ◽  
Betsy A. Hirsch ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Early Death ◽  
Gemtuzumab Ozogamicin ◽  
Juvenile Myelomonocytic Leukemia ◽  
Cell Transplant ◽  
Intensive Chemotherapy

Abstract Background: Infants <1 year of age with AML are at high risk of early death during induction, pulmonary and infectious toxicities, and treatment related mortality (TRM). Compared with older children, infants are more likely to have higher risk clinical and cytogenetic features. Targeted therapy is needed to improve the outcomes for infants with AML while minimizing toxicities. Objective: To determine if the addition of gemtuzumab ozogamicin (GO) to standard chemotherapy is safe, tolerable, and improves event free survival (EFS) in infants <1 year of age with AML. Methods: Infants >/= 1 month to <1 year of age with de novo AML or <1 month of age with progressive AML were eligible for enrollment on the COG trials AAML03P1 and AAML0531. Infants with acute promyelocytic leukemia, juvenile myelomonocytic leukemia, bone marrow failure syndromes, or Down syndrome were not eligible. The 5-course chemotherapy backbone was identical in both trials. GO 3 mg/m2/dose (0.1 mg/kg for patients with a body surface area <0.6 m2) was given on day 6 of Induction (Ind) I and day 7 of Intensification (Int) II to all patients on AAML03P1 and to randomized patients on the experimental arm of AAML0531. Patients on the control arm of AAML0531 were treated with standard therapy without GO (noGO). Stem cell transplant (SCT) was given following IntI to patients on AAML03P1 with a matched family donor (MFD) and to patients on AAML0531 with high risk (HR) disease or with intermediate risk (IR) disease and a MFD. SCT recipients only received one dose of GO. Patients were removed from protocol if the bone marrow had >/= 20% blasts after IndI on AAML03P1 or >/= 5% blasts after IndII on both studies. Early death (ED) was defined as death during IndI. Results: AAML03P1 enrolled 39 infants from 2003-2005 and AAML0531 enrolled 103 infants from 2006-2010 (Table 1). Median follow up was 5.02 years. The demographics and disease characteristics of infants enrolled on both studies were similar. Compared with enrolled children >/= 1 year of age, infants had higher frequencies of hepatomegaly (p<0.001), splenomegaly (p<0.001), hyperleukocytosis (WBC>100x103/µL, p=0.003) and French-American-British (FAB) M5 (p<0.001), and M7 (p<0.001) AML. Infants had less FAB M1 (p<0.001), M2 (p<0.001), and M4 (p=0.029) AML. There was no difference in CNS disease by age. The frequency of 11q23/MLL rearrangement was highest in infants 0-179 days of age (44%) and significantly decreased with increasing age (p<0.001). Favorable cytogenetics were rare in infants: t(8;21) was not found and inv(16)/t(16;16) was only found in 4 patients. FLT3-ITD HAR was absent in infants. The majority of infants (89%) fell into the IR group and infants were less likely to have had high (HR) or low risk (LR) disease when compared with children >/= 1 year. Table 1: Combined characteristics of infants on AAML03P1 and AAML0531 Table 1:. Combined characteristics of infants on AAML03P1 and AAML0531 The ED rate was higher in younger infants (7 ED, infants 0-179d) when compared with older infants (1 ED, infants 180-364d) (p=0.013). EDs were not increased in infants who received GO vs. noGO (5 vs. 3 ED, p=0.730). The complete remission (CR) rate for infants was 68% at the end of IndII. The 5 year EFS was lower in infants than children >/= 1 year (42 vs. 50%, p=0.001). The 5 year OS for infants was 62%, relapse risk (RR) was 44%, and TRM was 10%. Infants who received GO had improved OS, EFS, and RR, though the differences were not statistically significant (Table 2). Table 2: Combined outcomes of infants on AAML03P1 and AAML0531: noGO vs. GO Conclusion: GO in combination with intensive chemotherapy is tolerable in infants with AML, does not increase early deaths, and is associated with trends toward improved EFS, OS, and RR. Table 2:. Combined outcomes of infants on AAML03P1 and AAML0531: noGO vs. GO Conclusion: GO in combination with intensive chemotherapy is tolerable in infants with AML, does not increase early deaths, and is associated with trends toward improved EFS, OS, and RR. Disclosures No relevant conflicts of interest to declare.

Fractionated ICE with Rituximab Is Safe and Effective for Relapse/Refractory DLBCL Patients with Severe Comorbidities

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2713-2713
Author(s):  
Norina Tanaka ◽  
Yoichi Imai ◽  
Aya Watanabe ◽  
Kenjiro Mitsuhashi ◽  
Kentaro Yoshinaga ◽  
...  
Keyword(s):  
Survival Rate ◽  
Adverse Events ◽  
Salvage Therapy ◽  
Conflicts Of Interest ◽  
B Cell Lymphoma ◽  
Outpatient Clinics ◽  
Survival Duration ◽  
Salvage Regimen ◽  
Significant Difference ◽  
Severe Comorbidity

Abstract Background: Although many salvage regimens have been used in patients with relapse or refractory lymphoma, these have limitations in elderly or patients with complications due to toxicity and restricted tolerability. In particular, the treatment strategy for patients with severe comorbidity remains to be determined. The combination of ifosfamide, carboplatin, and etoposide (ICE) has been used for relapse and refractory non-Hodgkin lymphoma since the 1990s. Ifosfamide, an alkylating agent, is a key drug in the ICE regimen, which is non-cross resistant with cyclophosphamide. In practice, there are various regimens of ICE treatment. The outpatient-based fractionated regimen of ICE (fractionated ICE) described in 2003 by Herzberg et al involves a different method of ifosfamide-administration from that originally described. Although ifosfamide 5000 mg/m2 is continuously infused for 24 h according to the original ICE regimen, it is infused in three equally divided doses over 2 h on days 1-3 of each cycle in the fractionated ICE regimen. Unlike the original ICE regimen, the modified regimen can be performed in outpatient clinics. The efficacy and tolerability of fractionated ICE as both a salvage and stem cell mobilization regimen have been confirmed in relapse/refractory patients. Many studies have reported the efficacy of the addition of rituximab to chemotherapy for diffuse large B-cell lymphoma patients (DLBCL). However, no study has reported the efficacy of rituximab addition to the fractionated ICE regimen. In this study, we analyzed the efficacy and toxicity of fractionated ICE with rituximab (fractionated R-ICE) as a salvage regimen in relapse/refractory DLBCL patients (Table 1). Further, we compared the response and survival rate after fractionated R-ICE between patients with severe comorbidity and other patients. Method: We retrospectively analyzed the records of 66 patients with relapse or refractory DLBCL diagnosed between 2000 and 2014. Comorbidities were evaluated using Charlson Comorbidity Index (CCI), and National Cancer Institute Common Toxicity Criteria were used to define toxicities. Result: Among the 66 patients, 55 received salvage therapies, 30 received fractionated R-ICE, and 25 received it as a second-line salvage therapy. Efficacy and toxicity is demonstrated in Table 2. The overall response rate (ORR) to fractionated R-ICE was 46.7% (n=14) (complete response [CR], 26.7% [n=8], partial response, 20% [n=6]); 1 year survival rate after relapse was 56.7%, and the duration of 50% survival after relapse was 2.4 years. During the cycles, myelosuppression was the most serious toxicity, followed by grade 4 hematological adverse events were 18 (60%) patients, respectively. A previous study showed poor prognosis in patients with high CCIs before the first R-CHOP treatment. In our study, the ratio of patients with chemotherapy dose reduction less than 30% was comparable between low (0 or 1) and high (≥2) CCIs estimated before the fractionated R-ICE therapy. There was no significant difference of survival duration after relapse between low and high CCI (Figure 1). The items used for estimating CCI such as diabetes (n=5), heart disease (n=4), tumor (n=4), and collagen disease (n=3) did not affect survival. Conclusion: Although patients in our study were old (median: 71 y, range 50-85 y), the CR rate was similar to that of previous studies involving ICE therapy (CR rate 12.5-37%) or R-ICE therapy (CR rate 25-53%). Our results suggest that comorbidities do not have significant impact on the outcome of patients with relapse or refractory DLBCL treated with fractionated R-ICE. Although myelosuppression was severe in patients with high CCI scores, there was no increased incidence of infection or other adverse events. Fractionated R-ICE is supposed to be useful as a salvage therapy, which can be performed in outpatient clinics for relapse/refractory DLBCL patients including those who were older or having high CCI scores. Disclosures No relevant conflicts of interest to declare.

Factors Influencing Outcomes of Relapse from Front-Line Autologous Stem Cell Transplant (ASCT) over a 14 Year Period: A Single Centre Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3465-3465
Author(s):  
Selina J Chavda ◽  
Paul Michael Maciocia ◽  
Pavlina Mesiri ◽  
Nicholas Counsell ◽  
Jaimal Kothari ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Salvage Therapy ◽  
Cox Regression ◽  
Treatment Strategies ◽  
Autologous Stem Cell Transplant ◽  
Clinical Relapse ◽  
Cell Transplant ◽  
Salvage Regimen ◽  
Patient Counselling ◽  
Equity Ownership

Abstract Background. Chemotherapy followed by ASCT is standard of care in fit transplant-eligible newly diagnosed patients with Multiple Myeloma (MM). Most patients, however, will relapse and require further treatment. With increasing choice of therapies at relapse, we need to understand the determinants of treatment outcomes for these patients, to aid management decisions and patient counselling. Methods. This was a retrospective analysis of sequential patients who relapsed from upfront ASCT carried out between 2000-2014. PFS1 was defined as time from ASCT to 1st progression or death; PFS2, time from ASCT to 2nd progression or death and 2nd PFS, time from start of salvage regimen to 2nd progression or death. Post relapse survival (PRS) was measured from progression date and overall survival (OS) from ASCT date. Disease response, and adverse FISH were assigned according to IMWG. Survival was estimated using Kaplan- Meier curves and correlative analysis by Cox regression models. Results. Of 474 patients undergoing ASCT (2000-2014), 277 relapsed with a median age of 58 years (range 29-70).The M:F ratio was 1.85:1. Isotypes identified were: IgG 57.0%, IgA 22.7%, light chain 15.9%. Median PFS1 from ASCT was 20 months (0.47-128.3). ORR pre-ASCT was 91.3% (sCR/CR 4.4%, VGPR 25.4%) and post ASCT was 95.3% (sCR/CR 14.5%, VGPR 52.2%). At relapse, median age was 60 years (30-73) and 36.5% of patients had ISS stage2-3 disease. For the 277 patients who relapsed, median OS from ASCT was 67 months (CI 57-73) and median PRS was 40 months (35-44). PFS1 had a strong influence on OS, HR 0.97 (95%CI: 0.96-0.97, p<0.001), and PRS HR 0.99 (0.98-0.996, p=0.004). Patients relapsing before 2008 (prior to bortezomib funding) had shorter OS compared to those relapsing thereafter: median 61 vs 69 months, HR 1.38 (1.01-1.87, p=0.04). Depth of response (CR/VGPR) pre and post-ASCT were associated with longer PFS1- HR 0.70 (0.54-0.92, p=0.01), and HR 0.68(0.51-0.89, p=0.005) respectively, but not OS or PRS. 248 patients (89.5%) received systemic salvage therapy at relapse;106 patients (38.3%) experienced biochemical IMWG progression rather than clinical relapse, with median time to treatment of 5 months (2-64). Salvage regimens included: proteasome inhibitors(PIs) (64.5%), immunomodulatory agents (IMiDs, 29.8%, thalidomide-63.5%, lenalidomide-36.5%) and chemotherapy 5.2%; 26.6% of patients entered clinical trials and 13.7% underwent salvage ASCT. ORR was 70.4% (sCR/CR 10.9%, VGPR 31.6%). Median 2nd PFS was 17 months (16-20) and median PFS2 overall was 39 months (35-41). Achieving a deeper response to salvage treatment (CR/VGPR) was associated with a longer 2nd PFS (21 vs 17 months for PR, HR 0.65, 0.46-0.91, p=0.01), with a trend for PRS, HR 0.89(0.59-1.34, p=0.58) and OS, HR 0.77(0.51-1.17, p=0.22). Novel agents induced deeper responses, CR/VGPR with PI regimens 51.3%, with IMiDs 30%, and with chemotherapy 8%. Patients treated with PIs compared to all other systemic treatment regimens had a significantly longer OS of 80 vs 48 months, HR 0.60(0.43-0.85, p= 0.004). Patients entered into clinical trials (66) had deeper responses, ≥VGPR 61% compared to 31% in non-trial patients, and longer PRS, 64 vs 35 months, HR 0.54 (0.36-0.81, p= 0.003) and OS 90 vs 57 months, HR 0.50 (0.33-0.76, p=0.001). Risk factors at relapse influenced outcomes. Higher ISS was associated with shorter PRS, ISS 2/3 27 vs 50 months for ISS1, HR 2.52(1.74-3.66, p<0.0001) and OS, 46 vs 82 months, HR 2.42(1.67-3.50, p<0.0001). Presence of adverse FISH at relapse (54.1% of 133 patients) also predicted shorter PRS (restricted mean survival time 40 vs 72 months, p<0.001) and OS, 59 vs 97 months for standard FISH, HR 0.46 (0.28-0.73, p=0.0011). Adverse FISH at diagnosis (25.5% of 157) also predicted poorer outcomes. Conclusions. This real-world series shows that timing of relapse, period of relapse (pre-2008), ISS Stage, adverse FISH, and response to salvage regimen influence survival after relapse from frontline ASCT. Use of novel regimens, particularly PIs as salvage therapy post ASCT is associated with longer OS. Our data confirm the importance of entering patients into clinical trials. Multivariable linear regression analyses will be presented. Lastly, the inferior outcomes for patients with high-risk features highlights the need to develop different treatment strategies in this patient subgroup. Disclosures Maciocia: Autolus: Equity Ownership, Patents & Royalties: TRBC1 and 2 Targeting for the Diagnosis and Treatment of T-cell Malignancies. Yong:Janssen: Research Funding; Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor.

Tumor-Associated Macrophages Are Predictive of Survival in Relapsed and Refractory Hodgkin Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2630-2630 ◽  
Author(s):  
Carla Casulo ◽  
Maria Arcila ◽  
Julie Teruya-Feldstein ◽  
Jocelyn Maragulia ◽  
Craig H. Moskowitz
Keyword(s):  
Hodgkin Lymphoma ◽  
Salvage Therapy ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Cancer Center ◽  
Cell Transplant ◽  
Tumor Associated Macrophages ◽  
Tumor Biopsy ◽  
Tumor Specimen ◽  
Refractory Hodgkin Lymphoma

Abstract Abstract 2630 Background: Recent evidence has shown that an increased number of tumor-associated macrophages is associated with decreased survival in patients with classic Hodgkin lymphoma. Methods: Eighty-one patients treated for relapsed and refractory classical Hodgkin lymphoma at Memorial Sloan-Kettering Cancer Center from 1995 to 2003 were identified. Patients received either standard ICE based chemotherapy or a risk stratified salvage therapy approach based on the number of pre-salvage therapy risk factors present (B symptoms, extranodal disease, and/or remission duration less than 1 year). Patients were also evaluated by functional imaging with gallium or fluorodeoxy glucose positron emission tomography (FDG-PET), as well as computed tomography (CT) prior to both salvage therapy and autologous stem cell transplant (ASCT). Patients with at least minimal response to salvage therapy proceeded to ASCT. Paraffin embedded tissue blocks were obtained from each patient. A tissue microarray (TMA) of tumor samples was constructed with triplicate 0.6mm tissue cores. A 4um section of the TMA was stained by immunohistochemistry with the anti-CD68 antibody (Ventana, CONFIRM anti-CD68 [KP-1]) on the Ventana Discovery XT instrument following manufacturerÕs protocol. Staining was scored based on the percentage of CD68 positive cells compared to the total number of cells in selected representative areas. The final percent of CD68 positivity for each case was based on the average of the cores available for examination. Scoring was performed independently by two individuals (CC and MA). Results: Scores for CD68 positive tumor associated macrophages ranged from 0–74%. Patients were grouped into two categories based on scores of 0–29%, and >30%. Forty three percent of patients (35/81) had scores of 29% or less. Fifty six percent (46/81) had scores of 30% or greater. In the intent to treat population, patients with relapsed and refractory Hodgkin lymphoma and CD68 scores > 30% had shortened overall survival (OS) compared with scores < 30%; 4.5 years versus 12.2 years, respectively (p=.048). Patients proceeding to salvage ASCT with CD68 scores > 30% also had inferior OS compared with patients who had scores < 30%; 4.69 years versus 12.7 years (p=.015). Increased levels of CD68 tumor-associated macrophages also impacted progression free survival (PFS) in patients undergoing salvage therapy and ASCT. CD68 levels > 30% were associated with an inferior PFS. Patients with CD68 scores < 30% had a median PFS that was not reached, compared with 1.1 years for patients with scores > 30% (p=.03). Conclusions: Pre-salvage therapy tumor biopsy specimens with elevated levels of CD68 positive tumor-associated macrophage were associated with poor outcomes. Scores > 30% conferred an inferior OS and PFS for patients with relapsed and refractory Hodgkin lymphoma undergoing salvage therapy and ASCT. We believe this score can be used to risk stratify salvage therapy in transplant eligible patients with relapsed and refractory Hodgkin lymphoma. In future studies we will correlate the scores of the initial tumor specimen with that of the relapsed tumor specimen. Disclosures: No relevant conflicts of interest to declare.

Gemtuzumab Ozogamicin After Allogeneic Stem Cell Transplantation for Acute Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1970-1970
Author(s):  
Takeshi Kobayashi ◽  
Naoki Shingai ◽  
Shuntaro Ikegawa ◽  
Yukie Takahashi ◽  
Jun Aoki ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Maintenance Therapy ◽  
Cell Transplantation ◽  
Salvage Therapy ◽  
Conflicts Of Interest ◽  
Initial Response ◽  
Disease Recurrence ◽  
Gemtuzumab Ozogamicin ◽  
Hematopoietic Stem

Abstract Abstract 1970 Abstract Controversy abounds that anti-CD33 immunoconjugate, genutuzumab ozogamicin (GO) is really effective or not as a treatment for relapsed acute myeloid leukemia (AML). Consequently, GO is now commercially available in Japan, but not in USA or Europe. In this study, we have retrospectively analyzed the clinical impact of GO therapy as salvage or maintenance setting after allogeneic hematopoietic stem cell transplantation (allo-HSCT). During last 5 years, GO was given to 19 patients with AML as salvage therapy for disease recurrence (n = 15 patients) or maintenance therapy (n = 4 patients) after allo-HSCT in our institution. Clinical characteristics of these 19 patients are summarized (see Table): Median age was 44 years (range, 21–70 years). GO was basically administered at a dose of 3 mg/m2. The median cycle of GO therapy was 3 cycles (range, 1–12 cycles) and 3 cycles (range, 1–4 cycles) as salvage and maintenance therapy, respectively. GO was administered at a median of 205 days after allo-HSCT (range, 38–3,111 days) in the setting of salvage therapy, while as maintenance therapy, patients with high risk AML received GO as early as 29 days after allo-HSCT (range, 24–71 days). Two of 15 patients with recurrent disease achieved complete remission and 4 patients showed partial response (>50% decrease of bone marrow blast percentage). Thus, a total of 6 patients (40%) exhibited initial response to GO. However, 5 patients of them developed irreversible hepatic veno-occulusive disease (VOD) and eventually died at median of 146 days after GO therapy (range, 9–206 days). In view of 4 patients with maintenance therapy, 1 patient have faced to the subsequent disease relapse but no patients developed severe adverse effects including hepatic VOD and all patients are currently alive, albeit short follow-up. This small study demonstrates that GO offers an alternative tool for rescuing relapsed AML after allo-HSCT, but increases the risk of developing life-threatening hepatic VOD. Thus, further clarification is needed regarding which patients to treat with GO and at what dose of GO. Disclosures: No relevant conflicts of interest to declare.

Incidence and Outcomes of a Rare Translocation t(3,5) in Patients (pts) with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1456-1456
Author(s):  
Mona Lisa Alattar ◽  
Hagop M. Kantarjian ◽  
Jorge E. Cortes ◽  
Tapan M. Kadia ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Median Number ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Nras Mutation ◽  
Agent Based ◽  
Molecular Abnormalities ◽  
Novel Treatment

Abstract Abstract 1456 Background: Cytogenetic analysis of large pt cohorts allows us to evaluate the prognostic impact of rare and unique translocations. Little is known about the clinical outcomes of pts with t(3,5), which generally results in fusion of NPM and MLF1 in pts with MDS and AML. Methods: We retrospectively reviewed the charts of 8,215 pts with a diagnosis of MDS or AML evaluated at our institution from 1985–2011. Results: A total of 17 pts with a t(3,5) either at diagnosis or post-treatment were identified (10 pts, as the sole cytogenetic abnormality, and 7 pts, as part of other/complex karyotype). Among evaluable cases (15/17), frequently occurring breakpoints included q25;q34 (n=4), p21;q15 (n=2), and p21;q13 (n=2).10 pts had MDS with IPSS of Int-1(n=5) and Int-2(n=5), and 7 pts had AML. Four pts had therapy-related MDS (3 pts with prior lymphoma, 1 pt small cell lung cancer) and one pt with MDS had PNH. Median age was 56 years (range, 20–78) at diagnosis. Four pts (24%) had a FLT3-ITD mutation (3 with AML and 1 with MDS), 1 of these FLT3-mutated pts had additional mutations in c-KIT and NRAS mutation, 9 pts were tested and negative for molecular abnormalities, and 4 pts did not have molecular analysis available. Therapies were diverse, with two most common: cytarabine-based regimens (n=6) and hypomethylating agent-based therapy (n=6). Overall, median number of therapies for all pts was 1 (range, 0–5), including 2 pts treated with upfront stem cell transplant (SCT) and 1 pt treated with only growth factors/supportive care. Six pts (35%) (MDS 3 pts, AML 3 pts) underwent SCT during their course of therapy (including 1 cord blood, 1 SCT with NK cells, and 4 allogeneic MUD SCT). Overall median survival for pts with MDS was 8.1 months (range, 1–57) and for pts with AML, 21 months (range, 2–53). CR was achieved overall in 12 pts (71%) with median CR duration of 3.2 months (range, 1–60 months). Three (18%) pts were refractory to all chemotherapy and one pt died during induction chemotherapy (infection and diffuse alveolar hemorrhage). One pt never received treatment. Conclusions: Survival is particularly poor among patients with MDS and t(3;5) while those with AML have survival comparable to normal karyotype (NK) AML. Further investigation with novel treatment approaches is warranted in this subpopulation of MDS/AML pts. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Comparison of Salvage Chemotherapy Regimens in Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2708-2708
Author(s):  
Muhammad Umair Mushtaq ◽  
Sibgha Gull Chaudhary ◽  
Laura C. Michaelis ◽  
Karen-Sue B. Carlson ◽  
Sameem Abedin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Salvage Chemotherapy ◽  
Regression Analyses ◽  
Salvage Regimen ◽  
Baseline Characteristics ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract Background Induction therapy for acute myeloid leukemia (AML) with a cytarabine-anthracycline regimen (7+3) is well-established; however, there is no standard salvage therapy for patients with relapsed/refractory AML (RR-AML). There is a paucity of data regarding outcomes with salvage regimens in RR-AML that include cladribine, cytarabine, and filgrastim with mitoxantrone (CLAG-M) or without mitoxantrone (CLAG), and mitoxantrone, etoposide, and cytarabine (MEC). We compared outcomes of patients receiving CLAG-M, CLAG or MEC as salvage therapy for RR-AML. Methods A multi-center retrospective study was conducted, including 146 adult RR-AML patients who underwent salvage therapy at the University of Wisconsin and Medical College of Wisconsin from 2009 to 2018. Demographic, clinical and pathologic factors were ascertained at the time of RR-AML diagnosis. The Center for International Blood and Marrow Transplant Research (CIBMTR) response criteria were used. Refractory AML was defined as failure to achieve remission after one or more courses of induction chemotherapy. Minimal residual disease (MRD)-negative was defined by the absence of leukemic cells by morphology and flow cytometry (<0.01%). Data were analyzed using SPSS version 21 (SPSS Inc, Chicago, IL). Bivariate analyses, using chi-square and t-test, and logistic regression analyses were performed for baseline characteristics and response to salvage chemotherapy. Kaplan-Meier analyses, using the log-rank test, were conducted. Cox regression analyses were used to correlate factors with OS. Hazard ratios (HR) with 95% CI were obtained. Statistical significance was considered at P<0.05. Results The study included 146 patients with relapsed (57.5%, n=84) or refractory (42.5%, n=62) AML who received CLAG-M (51%, n=74), MEC (39%, n=57) or CLAG (10%, n=15) salvage chemotherapy. Baseline characteristics were similar between the three groups (all P>0.1). Median age was 60 years (range 22-77 years) and 59% patients were male. AML was classified according to WHO 2016 guidelines as AML with recurrent genetic abnormalities (23%), myelodysplasia (MDS)-related AML (25%), therapy-related AML (8%) and AML not otherwise specified (44%). Cytogenetics were good (5%), intermediate (60%) and poor (36%) with normal (41%), complex (25%), trisomy (8%) and monosomy 5 or 7 (5.5%) being common karyotypes. Among those who had molecular testing (n=119), NPM1 and FLT3-ITD were reported in 21% and 20% patients respectively. AML risk status was good (16%), intermediate (32%) and poor (52%), based on cytogenetic and molecular abnormalities as per ELN 2017 and NCCN 2018 guidelines. Extramedullary disease was present in 13% patients. Prior hematopoietic stem cell transplant (HSCT) was performed in 13% patients. Median lab values prior to salvage regimen were: hemoglobin 9.1 g/dL, platelets 49 K/uL, leukocytes 2.5 K/uL, LDH 231 U/L and bone marrow myeloblasts 28%. Overall response rate was 49% (CLAG-M 55%, n=41/74; MEC 44%, n=25/57, CLAG 40%, n=6/15) with complete remission (CR) rate of 46% (CLAG-M 54%, MEC 37%, CLAG 40%) [P=0.140]. Three percent patients (n=5; CLAG-M=1, MEC=4) had CR with incomplete hematologic recovery (CRi). MRD analysis was available for 83 patients and a trend was seen in MRD-negative CR rates favoring CLAG-M (44%) over MEC (25%) or CLAG (17%) [P=0.128]. Sixty-six patients (45%) received subsequent HSCT (CLAG-M 50%, n=37/74; MEC 44%, 25/57; CLAG 27%, n=4/15) [P=0.245]. At last follow-up, 34% patients were in CR (CLAG-M 42%, MEC 28%, CLAG 20%) [P=0.120]. Fifty (34%) patients were alive at last follow-up (CLAG-M 46%, MEC 23%, CLAG 20%) [P=0.010]. Median OS was 9.7 months (95% CI 6.8-12.6) that was significantly better with CLAG-M (13.3 months, 95% CI 2.4-24.3) compared to MEC (6.9 months, 95% CI 2.9-10.9) or CLAG (6.2 months, 95% CI 2.4-12.6) [P=0.025] Figure 1. In multivariate model adjusted for age, gender and refractory vs relapsed AML, MEC (HR 1.75, 95% CI 1.13-2.71, P=0.013) and CLAG (HR 1.97, 95% CI 1.02-3.79, P=0.043) regimens had worse OS compared to CLAG-M. After adjusting for age, gender, refractory vs relapsed AML and HSCT, CLAG-M remained independent predictor of better OS (HR 0.64, 95% CI 0.42-0.97, P=0.037). Conclusion CLAG-M compared to MEC or CLAG is associated with significantly better OS in RR-AML regardless of age, refractory vs relapsed AML and HSCT. Our findings support the use of CLAG-M as a preferred salvage regimen for RR-AML. Figure 1. Figure 1. Disclosures Atallah: Novartis: Consultancy; BMS: Consultancy; Jazz: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy.

All-Trans Retinoic Acid and Gemtuzumab Ozogamicin as Adjunct To Salvage Therapy in Primary Refractory Acute Myeloid Leukemia: Results of Consecutive Phase II Studies of the AMLSG.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1849-1849
Author(s):  
Richard F. Schlenk ◽  
Konstanze Doehner ◽  
Martina Kerz ◽  
Frank Hartmann ◽  
Francesco del Valle ◽  
...  
Keyword(s):  
Salvage Therapy ◽  
Odds Ratio ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Liver Toxicity ◽  
Salvage Chemotherapy ◽  
Gemtuzumab Ozogamicin ◽  
All Trans Retinoic Acid ◽  
Phase Ii Studies ◽  
Refractory Aml

Abstract Introduction: Response to first induction therapy is one of the most important prognostic factors in patients with adult myeloid leukemia (AML). Induction of CR or PR is the primary aim in these patients. Methods: Between 1993 and 2005 225 consecutive patients (median age: 48.4 yrs, range 16–60 yrs) treated within the AMLHD93 (n=45), AMLHD98A (n=157) and AMLSG 05-04 (n=23, still active) trials were evaluated. All patients had primary refractory AML after one cycle of ICE. The different salvage therapies were as follows: AMLHD93 sequential-HAM (S-HAM) for patients <55 years of age [cytarabine 3g/m2 bid. days 1,2,8,9, mitoxantrone 10mg/m2 days 3,4,10,11], HAM for patients >=55 years of age [cytarabine 3g/m2 bid., days 1–3, mitoxantrone 12mg/m2 days 2,3]; AMLHD98A: A-HAM [HAM with ATRA 45mg/m2 days 3–5, 15mg/m2 days 6–28]; AMLSG 05-04: GO-A-HAM [A-HAM with gemtuzumab ozogamicin 3g/m2 day 1]. Results: The distribution of the different salvage therapies was HAM n=21, S-HAM n=22, A-HAM n=117, GO-A-HAM n=23, other n=31 no further therapy n=11. Response according to salvage therapy was as follows: response GO-A-HAM A-HAM S-HAM HAM CR 11 (48%) 40 (34%) 5 (23%) 3 (14%) PR 4 (17%) 33 (28%) 5 (23%) 4 (19%) RD 6 (26%) 36 (31%) 12 (54%) 12 (57%) death 2 (9%) 8 (7%) 0 2 (10%) No CTC-grade 3-5 liver toxicity was seen in patients receiving GO-A-HAM. Multivariable analyses revealed that regimens containing ATRA (odds ratio 2.5, p=0.01) and cytogenetic subgroup [t(11q23) odds ratio 4.2 p=0.04 (n=13), non-complex high risk aberrations odds ratio 4.2 p=0.007 (n=34)] were associated with a significantly better response rate (subsuming CR and PR). 119 of 225 patients have received stem cell transplantation. No case of veno occlusive disease was in 10 so far transplanted pts who have had GO-A-HAM. Median survival was 10.7 months. Conclusions: Although retrospective in nature our study suggests that ATRA as adjunct to salvage chemotherapy in primary refractory AML patients improves the response rate. The addition of GO in a dosage of 3mg/m2 results in promising response rates without increasing toxicity.

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