Addition of All-Trans Retinoic Acid (ATRA) to the Combination of Fludarabine, Cytarabine, Idarubicin, with or without GCSF in Older, Higher Risk Patients with AML and High-Risk MDS Does Not Improve the Outcome in Those with NPM1 Mutation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2616-2616 ◽  
Author(s):  
Aziz Nazha ◽  
Carlos E. Bueso-Ramos ◽  
Stefan Faderl ◽  
Elihu H. Estey ◽  
Susan M. O'Brien ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
High Risk ◽  
Research Funding ◽  
Gene Mutations ◽  
Npm1 Mutation ◽  
Related Disease ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 2616 Background: Previous studies have been conflicting in their findings regarding whether NPM1 gene mutations may be a marker for response to all-trans retinoic acid (ATRA) given as an adjunct to intensive chemotherapy in patients with acute myeloid leukemia (AML) (Schlenk RF, Haematologica, 2009, 94, 54–60, Burnett AK, Blood, 2010, 115,948, and Schlenk RF, abstract #80, ASH 2011). Patients and Methods: we examined the impact of the addition of ATRA among patients with diploid cytogenetics treated on a randomized phase II study of fludarabine + cytarabine + idarubicine +/− GCSF +/− ATRA with available data on their NPM1 mutation status. Between September 1995 and November 1997, 215 patients with newly diagnosed AML (n=153) or high-risk MDS (RAEB or RAEB-T; n=62) were enrolled in the study. They had to have one of the unfavorable features of age > 71 years, antecedent hematological disorder (AHD), therapy- related disease, or high bilirubin (>2.9 mg/ml) or creatinine (>1.5 mg/ml) to be eligible to participate in the study (Estey E, Blood, 1999, 93, 2478). Among them 70 patients had diploid cytogenetic and are the subjects of this analysis. Results: The median age of the 70 patients was 66.5 (range, 23–87), 60% had AHD, 15.7% had therapy-related disease, and 40% were older than 71. Bone marrow samples were available for all patients for examination by immunohistochemistry (IHC) for the presence of cytoplasmic NPM (correlating to NPM1 mutation). Twenty (29%) of patients had NPM1 mutation. Among them 7 (35%) did and 13 (65%) did not receive ATRA in combination with chemotherapy. Complete remission (CR) was achieved in 5 (71.4%) of patients treated with ATRA as compared to 9 (69.2%) without ATRA (p=NS). The median event-free survival was 82 weeks vs. 56 weeks for patients receiving ATRA or not [(p=0.5), ranges, (10–173 weeks) and (1–646 weeks), respectively]. The median overall survival was 41 weeks vs. 60 weeks for patients receiving ATRA or not [(p=0.74), ranges, (3–452 weeks) and (0–735 weeks), respectively]. Conclusion: There was no significant difference in CR rate, EFS, or OS in this higher risk population of patients with NPM1 mutated diploid AML or high-risk MDS receiving ATRA as an adjunct to chemotherapy. Disclosures: Kantarjian: Genzyme: Research Funding. Ravandi:genzyme: Research Funding.

Role of Etoposide in Combination with All-Trans Retinoic Acid in the Treatment of Elderly Patients with Acute Myeloid Leukemia and NPM1 Mutation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 559-559 ◽  
Author(s):  
Marie-Luise Hütter ◽  
Konstanze Döhner ◽  
Ingo G.H. Schmidt-Wolf ◽  
Francisco Del Valle ◽  
Björn Heydrich ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Elderly Patients ◽  
Induction Therapy ◽  
De Novo ◽  
Npm1 Mutation ◽  
Mutation Status ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Significant Difference ◽  
The Impact

Abstract Rationale: In a previous randomized trial (AML HD98B) in elderly (>60 yrs) patients with AML (excluding APL), we could demonstrate that all-trans retinoic acid (ATRA) given as adjunct to intensive induction therapy with idarubicin, cytarabine and etoposide significantly improved outcome; this beneficial effect appeared to be restricted to patients having NPM1 mutation without concomitant FLT3-ITD (NPM1mut/FLT3-ITDneg). In our subsequent trial in elderly patients (AMLSG 06-04), all patients received ATRA with a similar backbone of chemotherapy, except that for induction therapy idarubicin was intensified and etoposide was omitted. NPM1mut AML is associated with myelomonocytic/monocytic differentiation, and etoposide is believed to have a particular effect in these morphologic subtypes of AML. Aims: To evaluate the impact of etoposide in combination with ATRA in elderly patients with AML exhibiting NPM1 mutation enrolled into two consecutive AMLSG protocols. Methods: 171 patients with NPM1mut AML were included in this retrospective analysis; 78 patients from trial AML HD98B (trial A; accrual from 1998 to 2004); and 95 patients from trial AMLSG 06-04 (trial B, 2004–2008). Twenty-nine of 78 (37%) patients and 87 of 93 (94%) received ATRA in trials A and B, respectively. Results: Initial patient characteristics, such as median age (67.8 and 67.9 years for trial A and B, respectively), type of AML (de novo, secondary or therapy-associated), white blood cell count (WBC), LDH, and FLT3-ITD mutation status (41% and 47%), were not significantly different between the two cohorts. The rates of complete remission (CR) were 68% and 71% for NPM1mut patients in trial A and B, respectively. Lower age and lower WBC counts were significantly associated with achievement of CR; study, treatment with ATRA, type of AML, and FLT3-ITD mutation status had no impact. Univariable survival analyses revealed no significant difference for the end points event-free (EFS), relapse-free (RFS) and overall survival (OS) between the two patient cohorts from trial A and B. However, when restricting the analysis to patients who had received ATRA, a significant better EFS (p=0.05) and RFS (p=0.03) was found for patients with the genotype NPM1mut/FLT3-ITDneg in trial A (that included etoposide) compared to trial B (in which etoposide was omitted); there was no difference in EFS (p=0.18) and RFS (p=0.09) for patients with the genotype NPM1mut/FLT3-ITDpos. In addition, no difference was seen either in patients with the genotype NPM1mut/FLT3-ITDpos or in patients with the genotype NPM1mut/FLT3-ITDneg in terms of OS mainly due to a high second CR rate in patients with the genotype NPM1mut/FLT3-ITDneg. Conclusion: The data from this retrospective subgroup analysis suggest that etoposide in combination with ATRA may exert a beneficial synergistic effect in elderly patients with AML having NPM1 mutation without concurrent FLT3-ITD.

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.

The Genotype NPM1mut/FLT3-ITDneg Is a Highly Significant Predictive Factor for Response to Therapy with All-Trans Retinoic Acid in Acute Myeloid Leukemia - Results from AMLSG Trial AML HD98B.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 297-297 ◽  
Author(s):  
Richard F. Schlenk ◽  
Konstanze Döhner ◽  
Michael Kneba ◽  
Francesco del Valle ◽  
Frank Hartmann ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Beneficial Effect ◽  
Predictive Factor ◽  
De Novo ◽  
Response To Therapy ◽  
Tyrosine Kinase Domain ◽  
Npm1 Mutation ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
The Impact

Abstract Background: In a previous randomized trial (AML HD98B) of the AMLSG in elderly (>60 yrs) patients with AML (excluding APL), we could demonstrate that all-trans retinoic acid (ATRA) given as adjunct to intensive chemotherapy significantly improved complete remission (CR) rate and overall survival (OS). Our hypothesis for this study was that this beneficial effect of ATRA may be confined to a specific genotypic subset of AML. Aims: To evaluate the impact of ATRA on clinical outcome in cytogenetic and molecular genetic subsets of AML. Methods: Between 1998 and 2004, a total of 372 patients were enrolled. 242 patients were randomized for ATRA as adjunct to intensive induction (idarubicin, cytarabine, etoposide) and first consolidation therapy (intermediate-dose cytarabine) (Schlenk et al., Leukemia 2004), followed by a second randomization between further intensive consolidation versus a one-year oral maintenance therapy (Schlenk et al., Leukemia 2006). After an interim analysis in 2003, first randomization was stopped; the following 130 patients received chemotherapy without ATRA. Data from conventional cytogenetics and from fluorescence in-situ hybridization were previously reported (Fröhling et al., Blood 2006). All available leukemia specimens were analyzed for mutations in the genes encoding NPM1, CEBPA, and FLT3. Results: Median age of the 372 patients was 67 years (range: 61 to 83 yrs); median follow-up time was 68 months. 67% of the patients had de novo AML, 33% had secondary AML. Incidences of mutations were as follows (no. of specimens analyzed): NPM1 mutation, 25% (n=242); FLT3 internal tandem duplication (ITD), 18% (n=263); FLT3 tyrosine kinase domain mutation, 5% (n=244); CEBPA mutation, 8% (CEBPA analyzed only in normal karyotype samples; n=109). Logistic regression analysis performed on all patients identified three significant variables for achievement of CR: the genotype NPM1mut (OR 2.6; 95%-CI, 1.2–5.5), non-adverse karyotype subsuming core-binding factor and cytogenetically normal AML (OR 2.7; 95%-CI, 1.4–4.9); and age (diff. of 10 years, OR 0.58; 95%-CI, 0.3–1.0). Cox proportional hazard model for OS was performed on patients who were up-front randomized for ATRA. This model revealed a significant interaction between ATRA and the NPM1mut/FLT3-ITDneg genotype, confining the beneficial effect of ATRA to patients in that subgroup (HR, 0.29; 95%-CI, 0.10–0.87). Additional variables were log(LDH) (HR, 2.6; 95%-CI, 1.4 – 4.6), age (HR, 1.6; 95%-CI, 1.2– 2.2) and non-adverse karyotype (HR, 0.7; 95%-CI, 0.5–1.0). Univariable analysis revealed a survival after 5 years in patients with the genotype NPM1mut/FLT3-ITDneg of 57% (95%-CI, 28%–78%) in the ATRA-arm (n=16) compared to only 6% (95%-CI, 0%–25%) in the standard-arm (n=14) (p=0.002). In contrast, there was no difference in survival in all other patients with a survival of 2% (95%-CI, 0%–7%) in both arms (p=0.23). Conclusions: The genotype NPM1mut/FLT3-ITDneg emerges as highly significant predictive factor for response to ATRA in elderly patients with AML. This finding is validated prospectively in the ongoing AMLSG 07–04 study randomizing for ATRA in younger adults (ClinicalTrials.gov Identifier: NCT00151242).

scholarly journals Oral arsenic and all-trans retinoic acid for high-risk acute promyelocytic leukemia

Blood ◽  
2018 ◽  
Vol 131 (26) ◽  
pp. 2987-2989 ◽  
Author(s):  
Hong-Hu Zhu ◽  
Yan-Rong Liu ◽  
Jin-Song Jia ◽  
Ya-Zhen Qin ◽  
Xiao-Su Zhao ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
High Risk ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Retinoic Acid Syndrome in Patients with Acute Promyelocytic Leukemia Treated with All-Trans Retinoic Acid and Anthracycline Monochemotherapy.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2010-2010
Author(s):  
Pau Montesinos ◽  
Juan Bergua ◽  
Guillermo Martin ◽  
Javier de la Serna ◽  
Edo Vellenga ◽  
...  
Keyword(s):  
Renal Failure ◽  
Prognostic Factors ◽  
Retinoic Acid ◽  
Weight Gain ◽  
High Risk ◽  
Pleural Effusion ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Retinoic Acid Syndrome

Abstract Retinoic acid syndrome (RAS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all-trans retinoic acid (ATRA). Incidence of RAS has been reported ranging from 2% to 30%. It has been suggested that patients with leukocytes >5 x109/L at presentation are at high risk for the development of RAS. The impact of RAS on long term outcome is still a matter of controversy. We analyze the incidence, prognostic factors and outcome of RAS in 733 patients with newly diagnosed APL enrolled in the PETHEMA LPA96 and LPA99 trials (175 and 558 patients, respectively). Induction therapy consisted of ATRA and idarubicin, followed by three consolidation courses of anthracycline monochemotherapy. In the LPA99 trial, ATRA was added in each cycle of consolidation, except for low-risk patients. In the LPA99 trial, all patients received RAS prophylaxis with oral prednisone (0.5 mg/kg). Temporary discontinuation of ATRA and treatment with intravenous dexamethasone were recommended at the first signs of suspected RAS, in both trials. Definite RAS was defined as the presence of at least four of the following criteria: unexplained fever, respiratory distress, radiological pulmonary infiltrates, pericardial/pleural effusion, hypotension, renal failure, and weight gain over 5 kg. Overall, 87 patients (12%) experienced RAS, after a median of 6 days of ATRA (range, 0 to 46). Forty-seven cases (54%) occurred from days 0 to 7, 4 (5%) from days 8 to 14, 32 (36%) from days 15 to 30, and 4 (5%) from days 31 to 46. The main clinical signs were pulmonary infiltrates (83%), fever (80%), weight gain (74%), pleural effusion (63%) and renal failure (49%). ATRA was discontinued in 63% of patients. RAS was associated with age >50 years (41% vs 29%, p=0.02), serum level of creatinine >1.4 mg/dl (9% vs 3%, p<0.01) and leukocytes at presentation >5x109/L (46% vs 32%, p=0.01). Leukocytes >5x109/L and creatinine >1.4 mg/dl remained as independent prognostic factors in multivariate analysis. The incidence of RAS was not statistically different between the LPA96 (without prednisone prophylaxis) and LPA99 trials (15% vs 11%, p=0.16). RAS was associated with induction death (26% vs 7%, p<0.01) and was the main cause of death in 10 patients (1.4%). Age >60 years, leukocytes >10x109/L, RAS, male gender and serum creatinine level >1.4 mg/dl at presentation were independent prognostic factors for induction death. Patients developing RAS had a higher cumulative incidence of relapse (CIR) in the LPA96 trial (40% vs 15%, p<0.01), but there were no significant differences in the LPA99 trial (12% vs 13%). In conclusion, we have observed a bimodal peak incidence of RAS during the induction phase, with the first peak from days 0 to 7 and the second peak from days 15 to 30. Patients with leukocytes >5x109/L and serum creatinine level >1.4 mg/dl are at high risk for development of RAS, which is an adverse prognostic factor for induction death. The negative impact of RAS on CIR among patients treated with the LPA96 trial was not observed in the LPA99, in which patients received additional doses of ATRA for consolidation therapy.

Incidence, Outcome and Risk Factors of Pseudotumor Cerebri after All- Trans Retinoic Acid and Anthracycline-Based Chemotherapy in Patients with Acute Promyelocytic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2992-2992 ◽  
Author(s):  
Pau Montesinos ◽  
Edo Vellenga ◽  
Aleksandra Holowiecka ◽  
Chelo Rayon ◽  
Gustavo Milone ◽  
...  
Keyword(s):  
Risk Factors ◽  
Retinoic Acid ◽  
Side Effects ◽  
High Risk ◽  
Pseudotumor Cerebri ◽  
Promyelocytic Leukemia ◽  
Consolidation Therapy ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Risk Patients

Abstract Background: Pseudotumor cerebri associated with all-trans-retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) have been frequently described in pediatric patients. However, the incidence, outcome and risk factors of pseudotumor cerebri in APL are not well-known. We analyze the incidence and risk factors of this complication in a large series of patients with newly diagnosed APL enrolled in three consecutive trials of the PETHEMA Group (LPA96, LPA99 and LPA2005). Mehods: AIDA regimen (ATRA 45 mg/m2/d [25mg/m2/d in patients younger than 20] until CR and idarubicin 12 mg/m2/d on days 2, 4, 6 and 8) was given as induction therapy. Patients in CR received 3 monthly courses of risk-adapted consolidation therapy: idarubicin 5 mg/m2/d × 4 (course #1), mitoxantrone 10 mg/m2/d × 5 (course #2), and idarubicin 12 mg/m2/d × 1 (course #3). Since November 1999 (LPA99 trial), for patients with intermediate or high risk of relapse (Sanz et al, Blood 2000), consolidation was slightly intensified by increasing idarubicin doses in courses #1 and #3, and by simultaneously administering 25 mg/m2 ATRA together with chemotherapy in all three courses. Since July 2005, consolidation therapy in the ongoing LPA 2005 trial included the following modifications: the administration of ATRA for all patients; for low- and intermediate-risk patients, mitoxantrone has been reduced from five to three days in the second course; and for high-risk patients, cytarabine has been added to idarubicin in the first and third course. Maintenance therapy consisted of 50 mg/m2/d mercaptopurine orally, 15 mg/m2/week methotrexate intramuscularly, and 25 mg/m2/d ATRA for 15 days every three months. Diagnosis of pseudotumor cerebri was made in the presence of signs and symptoms of intracranial hypertension without clinical or radiological evidence of infective or space occupying lesions. Results: Of 1034 patients enrolled between November 1996 and July 2008, 32 (3%) experienced pseudotumor cerebri. Headaches without pseudotumor were present in 252 patients (25%). Thirty cases of pseudotumor occurred during induction therapy and 2 cases manifested only during consolidation. In all, 9 of 32 patients (28%) had recurrent pseudotumor cerebri after reinitiating ATRA. All these side effects were transient, reversible, and never a cause of death. CR rates were 96% and 90% in patients with and without pseudotumor cerebri, respectively (p=0.32). The incidence of pseudotumor cerebri among patients younger than 18 years, 18–25 years, 25–50 years and older than 50 years was 13%, 7%, 2% and 0.3%, respectively (p&lt;0.0001). There was a trend toward a correlation between fibrinogen &lt;170 mg/dL and worse general state (ECOG&gt;1) at presentation and development of pseudotumor cerebri (p=0.08 and p=0.06, respectively). We did not found any significant association between pseudotumor cerebri and WBC, platelets, relapse risk-score, hemoglobin, creatinine, PETHEMA trial, gender, morphological subtype, PML/RARA isoform, FLT3 mutations, and surface antigens (CD2, CD11b, CD13, CD15, CD34, CD56, and CD117). Conclusion: This study shows an overall incidence of pseudotumor cerebri of 3% among APL patients treated with ATRA and anthracycline-based regimens, with higher incidences in children and young adults (13% and 7%, respectively). No other prognostic factors could be demonstrated. The development of pseudotumor cerebri was not associated with a worse induction outcome. Side effects were reversible and transient, but roughly a third of patients had recurrent pseudotumor cerebri after reinitiating ATRA

Alemtuzumab Plus Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Transplantation in Ultra High-Risk CLL: Interim Analysis of a Phase II Study of the GCLLSG and fcgcll/MW

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2854-2854 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Florence Cymbalista ◽  
Véronique Leblond ◽  
Alain Delmer ◽  
Dirk Winkler ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Response Rates ◽  
Long Term Results ◽  
High Dose ◽  
Significant Difference ◽  
Ultra High Risk ◽  
Grade 3 ◽  
The Impact

Abstract Abstract 2854 Alemtuzumab (A) proved to be efficacious in CLL patients (pts) with very poor prognosis, either due to fludarabine (F) refractoriness or due to unfavorable cytogenetics (17p-). However, rate and duration of remissions still remain unsatisfactory. Therefore, the French and German CLL study groups jointly embarked on this trial, trying to achieve higher overall response rates (ORR) by adding high-dose dexamethasone (D) to A and, simultaneously, investigating the consolidation effect of prolonged A maintenance or allogeneic stem-cell transplantation (allo-SCT), respectively. Induction treatment consisted of subcutaneous A 30 mg weekly × 3 for 28 days, combined with oral D 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg on days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or A maintenance with 30 mg every 14 days for up to 2 years (y), at the discretion of pt and physician. Between January 2008 and July 2011, 124 pts were recruited at 26 centers, 120 of whom were eligible. Pts were generally subdivided into three cohorts: 55 pts were refractory (i.e. no response or relapse within 6 months) to regimens containing F or a similar drug (i.e. pentostatin, cladribine, bendamustine). Non-refractory pts all exhibited 17p- and had either untreated (n=39) or relapsed CLL (n = 26) requiring therapy. The median age was high with 66/64/66 y in 17p- 1st line, 17p- relapse, and F-refractory pts, respectively. The three cohorts had 46/54/75% Binet C disease, 41/35/27% B symptoms, 38/42/53% reduced performance status (ECOG 1/2), median thymidine kinase levels of 35/49/24 U/L, median ß2MG levels of 3.8/5.5/4.6 mg/L, and IGHV was unmutated in 89/96/87%. In the F-refractory group, 53% exhibited 17p deletion and 22% had 11q deletion. Pretreated patients had received a median of 3 (F-refractory) or 2 prior lines (17p- relapse). 5 pts had previously undergone autologous and 1 pt allo-SCT. Treatment and efficacy data are currently available for 87 pts who completed induction therapy :17p- 1st-line (n=30), 17p- relapse (n=17), and F-refractory (n=40). Of these, 80/53/55% received the full induction of 12 weeks. ORR (best observed status) was generally high with 97/76/70%. CR was achieved in 20/0/5%. After a median follow-up of 11.8 months (mo), median progression-free survival (PFS) was 16.9/10.4/8.4 mo. Deaths are recorded in 13/27/36% of pts, with median overall survival (OS) not yet reached (>24 mo) in the 17p- 1st line group, and 15/12 mo in 17p- relapse/F-refractory pts. Consolidation treatment was performed as maintenance A (median duration 32 weeks, range 2 – 89) in 34%, and allo-SCT in 30%, with a median age of 66 and 61 y in these subgroups. The main reasons for going off-study without consolidation were death due to infection (14%, n=11, of these 6 without response, and 10 in the F-refractory cohort), CLL progression (12%), and other toxicity (5%). Among the 28 pts not receiving consolidation, there were 19 (68%) deaths, 15 of them in the F-refractory cohort. When comparing A maintenance and allo-SCT for consolidation, there were 9 (35%) and 7 (30%) PD events, respectively and there was so far no significant difference in PFS (median 17 mo in both groups) or OS. During induction, grade 3/4 hematotoxicity consisted of anemia in 28%, neutropenia in 47%, and thrombopenia in 44%. Grade 3/4 non-CMV infection occurred in 29% of 17p- 1st-line, 15% of 17p- relapsed, and 56% of F-refractory pts. CMV reactivation was observed in 54/25/40%, without severe sequelae recorded. During A maintenance, grade 3/4 toxicity consisted of neutropenia in 39% pts and thrombopenia in 4% pts with 6 SAEs (ITP, diarrhea, infection, erythema, tachycardia, and thrombosis). Conclusions: The combination of A and D shows high response rates in ultra high-risk CLL, with promising preliminary findings for PFS and OS, despite the high median age of the pts. The results compare favorably to ORR/CR of 68%/5%, and median PFS of 11.3 mo in the 17p- subgroup of the CLL8 study treated with FCR, consisting of younger pts (median 61 y). In F-refractory CLL however, when compared to the preceding CLL2H study with single agent A, the improved initial response by adding dexamethasone does not seem to translate into improved long-term results. More mature follow-up is needed, especially with respect to the impact of allo-SCT. Disclosures: Stilgenbauer: Amgen: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: Alemtuzumab in 1st line CLL treatment. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding. Hinke:WiSP (CRO): Employment.

scholarly journals Effective Treatment of Acute Promyelocytic Leukemia With All-Trans-Retinoic Acid, Arsenic Trioxide, and Gemtuzumab Ozogamicin

2009 ◽  
Vol 27 (4) ◽  
pp. 504-510 ◽  
Author(s):  
Farhad Ravandi ◽  
Eli Estey ◽  
Dan Jones ◽  
Stefan Faderl ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
High Risk ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Promyelocytic Leukemia ◽  
Platelet Recovery ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Purpose We examined the outcome of patients with newly diagnosed acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) with or without gemtuzumab ozogamicin (GO) but without traditional cytotoxic chemotherapy. Patients and Methods From February 2002 to March 2008, 82 patients with APL were treated with a combination of ATRA plus ATO. The first cohort of 65 patients received ATRA and ATO (beginning on day 10 of ATRA). High-risk patients (WBCs ≥ 10 × 109/L) received GO on the first day. From July 2007, the second cohort of 17 patients received ATRA and ATO concomitantly on day 1. They also received GO on day 1, if high risk, and if their WBC increased to more than 30 × 109/L during induction. Monitoring for PML-RARA fusion gene was conducted after induction and throughout consolidation and follow-up. Results Overall, 74 patients achieved complete remission (CR) and one achieved CR without full platelet recovery after the induction, for a response rate of 92%. Seven patients died at a median of 4 days (range, 1 to 24 days) after inclusion in the study from disease-related complications. The median follow-up is 99 weeks (range, 2 to 282 weeks). Among the responding patients, three experienced relapse at 39, 52, and 53 weeks. Three patients died after being in CR for 14, 21, and 71 weeks, all from a second malignancy. The estimated 3-year survival rate is 85%. Conclusion The combination of ATRA and ATO (with or without GO) as initial therapy for APL was effective and safe and can substitute chemotherapy-containing regimens.

Sign in / Sign up

Export Citation Format

Share Document