Presenting White Blood Cell Count and Kinetics of Molecular Remission Predict Prognosis in Acute Promyelocytic Leukemia Treated With All-Trans Retinoic Acid: Result of the Randomized MRC Trial

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4131-4143 ◽  
Author(s):  
Alan K. Burnett ◽  
David Grimwade ◽  
Ellen Solomon ◽  
Keith Wheatley ◽  
Anthony H. Goldstone
Keyword(s):  
Retinoic Acid ◽  
Promyelocytic Leukemia ◽  
Rt Pcr ◽  
Blood Cell Count ◽  
Relapse Risk ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
To Receive ◽  
Risk Of Relapse

Abstract All-trans retinoic acid (ATRA) is an essential component of the treatment of acute promyelocytic leukemia (APL), but the optimal timing and duration remain to be determined. Molecular characterization of this disease can refine the diagnosis and could be potentially useful in monitoring response to treatment. Patients defined morphologically to have APL were randomized to receive a 5-day course of ATRA before commencing chemotherapy or to receive daily ATRA commencing with chemotherapy and continuing until complete remission (CR). The chemotherapy was that used in current MRC Leukaemia Trials. Outcome comparisons were by intention to treat with additional analysis for relevant risk factors. Patients were characterized by molecular techniques for the fusion products of the t(15;17) and monitored by reverse transcriptase-polymerase chain reaction (RT-PCR) during and after treatment. Two hundred thirty-nine patients were randomized. Treatment with extended ATRA resulted in a superior remission rate (87% v 70%, P < .001), due to fewer early and induction deaths (12% v 23%, P = .02), and less resistant disease (2% v 7%, P = .03), which was associated with a significantly more rapid recovery of neutrophils and platelets. Extended ATRA reduced relapse risk (20%v 36% at 4 years, P = .04) and resulted in superior survival (71% v 52% at 4 years, P = .005). Presenting white blood cell count (WBC) was a key determinant of outcome. The 70% of patients who presented with a WBC less than 10 × 109/L had a better CR (85% v62%, P = .0001) and reduced relapse risk (22% v42%, P = .002) and superior survival (69%v 43%, P < .0001). Within the low count group, extended ATRA resulted in a better CR (94% v 76%, P= .001), reduced relapse risk (13% v 35%, P = .04), and improved survival (80% v 57%, P = .0009). There was no evidence of benefit in patients presenting with a higher WBC (>10 × 109/L). Molecular monitoring after the third chemotherapy course had a correlation with risk of relapse. The relapse risk was 57% if the RT-PCR was positive versus 27% if the RT-PCR was negative (P = .006). APL patients who present with a low WBC derive substantial benefit from combining ATRA with induction chemotherapy until remission is achieved, whereas patients with a higher WBC did not benefit. Molecular characterization of disease can improve diagnostic precision and a positive RT-PCR after consolidation identifies patients at a higher risk of relapse.

Presenting White Blood Cell Count and Kinetics of Molecular Remission Predict Prognosis in Acute Promyelocytic Leukemia Treated With All-Trans Retinoic Acid: Result of the Randomized MRC Trial

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4131-4143 ◽  
Author(s):  
Alan K. Burnett ◽  
David Grimwade ◽  
Ellen Solomon ◽  
Keith Wheatley ◽  
Anthony H. Goldstone
Keyword(s):  
Retinoic Acid ◽  
Promyelocytic Leukemia ◽  
Rt Pcr ◽  
Blood Cell Count ◽  
Relapse Risk ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
To Receive ◽  
Risk Of Relapse

All-trans retinoic acid (ATRA) is an essential component of the treatment of acute promyelocytic leukemia (APL), but the optimal timing and duration remain to be determined. Molecular characterization of this disease can refine the diagnosis and could be potentially useful in monitoring response to treatment. Patients defined morphologically to have APL were randomized to receive a 5-day course of ATRA before commencing chemotherapy or to receive daily ATRA commencing with chemotherapy and continuing until complete remission (CR). The chemotherapy was that used in current MRC Leukaemia Trials. Outcome comparisons were by intention to treat with additional analysis for relevant risk factors. Patients were characterized by molecular techniques for the fusion products of the t(15;17) and monitored by reverse transcriptase-polymerase chain reaction (RT-PCR) during and after treatment. Two hundred thirty-nine patients were randomized. Treatment with extended ATRA resulted in a superior remission rate (87% v 70%, P < .001), due to fewer early and induction deaths (12% v 23%, P = .02), and less resistant disease (2% v 7%, P = .03), which was associated with a significantly more rapid recovery of neutrophils and platelets. Extended ATRA reduced relapse risk (20%v 36% at 4 years, P = .04) and resulted in superior survival (71% v 52% at 4 years, P = .005). Presenting white blood cell count (WBC) was a key determinant of outcome. The 70% of patients who presented with a WBC less than 10 × 109/L had a better CR (85% v62%, P = .0001) and reduced relapse risk (22% v42%, P = .002) and superior survival (69%v 43%, P < .0001). Within the low count group, extended ATRA resulted in a better CR (94% v 76%, P= .001), reduced relapse risk (13% v 35%, P = .04), and improved survival (80% v 57%, P = .0009). There was no evidence of benefit in patients presenting with a higher WBC (>10 × 109/L). Molecular monitoring after the third chemotherapy course had a correlation with risk of relapse. The relapse risk was 57% if the RT-PCR was positive versus 27% if the RT-PCR was negative (P = .006). APL patients who present with a low WBC derive substantial benefit from combining ATRA with induction chemotherapy until remission is achieved, whereas patients with a higher WBC did not benefit. Molecular characterization of disease can improve diagnostic precision and a positive RT-PCR after consolidation identifies patients at a higher risk of relapse.

scholarly journals Molecular Profiling: A Case ofZBTB16-RARAAcute Promyelocytic Leukemia

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Stephen E. Langabeer ◽  
Lisa Preston ◽  
Johanna Kelly ◽  
Matt Goodyer ◽  
Ezzat Elhassadi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Clinical Course ◽  
Molecular Profiling ◽  
Promyelocytic Leukemia ◽  
Fusion Product ◽  
Rare Form ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Generation Sequencing

Several variantRARAtranslocations have been reported in acute promyelocytic leukemia (APL) of which the t(11;17)(q23;q21), which results in aZBTB16-RARAfusion, is the most widely identified and is largely resistant to therapy with all-trans retinoic acid (ATRA). The clinical course together with the cytogenetic and molecular characterization of a case of ATRA-unresponsiveZBTB16-RARAAPL is described. Additional mutations potentially cooperating with the translocation fusion product in leukemogenesis have been hitherto unreported inZBTB16-RARAAPL and were sought by application of a next-generation sequencing approach to detect those recurrently found in myeloid malignancies. This technique identified a solitary, low level mutation in theCEBPAgene. Molecular profiling of additional mutations may provide a platform to individualise therapeutic management in patients with this rare form of APL.

Clinical Observation on the Efficacy of All-Trans Retinoic Acid (ATRA) Combined with Arsenic Trioxide (As2O3) in Newly Diagnosed Acute Promyelocytic Leukemia (APL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 888-888 ◽  
Author(s):  
Y.F. Liu ◽  
Z.X. Shen ◽  
J. Hu ◽  
Y.M. Zhu ◽  
J.M. Li ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Promyelocytic Leukemia ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Rt Pcr ◽  
Front Line ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Fold Reduction

Abstract PURPOSE: To determine the efficacy of front-line use of all-trans retinoic acid (ATRA) combined with arsenic trioxide (As2O3) in patients with newly diagnosed acute promyelocytic leukemia (APL). PATIENTS AND METHODS: Since 2001, 61 patients have received ATRA (25mg/m2) and As2O3 (0.16mg/kg) daily till CR and all patients received 3 consolidation chemotherapy and then received 5 cycles of sequential treatment of ATRA, As2O3 and 6-MP/MTX. The efficacy of treatment protocol in induction remission, molecular response and relapse-free survival were compared with our historical control. RESULT: 58 (95.1%) patients achieved CR and all remain relapse free with the current protocol. Though ATRA/As2O3 duet did not improve the hematological/molecular remission rate and reduced the early mortality after induction, it did induce an early hematological response (26.1±4.1 days). During limited follow-up (20 to 39 months), both RFS and OS are significantly increased in patients who received the ATRA/As2O3/chemotherapy triad as post-remission therapy compared to the historical control. PML-RARa mRNA was retrospectively assessed by quantitative real-time reverse transcription-polymerase chain reaction (RQ-RT-PCR) before treatment, after CR, after consolidation and during follow-up period in 36 patients with ATRA and As2O3 combination treatment. PML-RARa normalized dose was found to be more significantly decreased after remission induction (median fold reduction: 335.8), and after consolidation (median fold reduction: 358362.2), as compared with ATRA or As2O3 mono-therapy. The addition of As2O3 into post-remission therapy can further increase the post-remission molecular response through either qualitative or quantitative RT-PCR measurement. CONCLUSION: Our current follow-up data suggested a potential benefit of front-line combination of ATRA and As2O3, which might translate into better chance of curing the disease.

PML/Rara and Rara/PML Chimeric Genes On Derivative Chromosome 17 In a Patient With Acute Promyelocytic Leukemia With Atypical t(15;17)(q11;q21)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4960-4960
Author(s):  
Pablo Lopez ◽  
Solange Simonet ◽  
Gerardo Romanelli ◽  
Daniela Infante ◽  
Analía Sanguinetti ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Retinoic Acid ◽  
Who Classification ◽  
Fusion Gene ◽  
Promyelocytic Leukemia ◽  
Chromosome 15 ◽  
Rt Pcr ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Blast Cells

Abstract Introduction Acute promyelocytic leukemia (APL) of the WHO classification is genetically characterized by the t(15;17)(q22;q21) chromosomal translocation involving the retinoic acid receptor alpha (RARA) located on band 17q21 and the promyelocytic leukemia gene (PML) on band 15q24 , leading to the PML/RARA fusion transcript, and by sensitivity of blast cells to all-trans retinoic acid or arsenic trioxide (ATO) targeted therapy. Although the vast majority of APL cases present with t(15;17)(q24;q21), formerly (q22;q21), a few patients have either simple or complex variants of this translocation involving chromosome 15, 17 and one or more other chromosomes. Analysis of these variant translocations is of great interest because they may mask a cryptic t(15;17) leading to misdiagnose a true APL as non APL-AML with other translocations involving RARA but not PML do exist, as mentioned in the WHO classification, and generally these cases do not respond to ATRA or ATO therapy and require more intensive chemotherapy. In these cases, the PML/RARA fusion gene can be identified by molecular analyses such as reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH). Case report 29-year-old man presented with dizziness and tiredness. Physical examination: organomegaly was not observed. Peripheral blood: hemoglobin concentration, 71 g/L; platelet count, 10x109/L white blood cell count (WBC) 0.5x109/L. Bone marrow aspirate showed 56% blast cells with Auer rods. Coagulation tests were normal. Leukemic cells were CD13+, CD33+, CD34-, CD117+ and HLA-DR-. Cytogenetic analysis by G-banding performed in bone marrow metaphase cells afforded the following karyotype: 46,XY, t(15;17)(q11;q21) with derivative (der) (15) shorter and der(17) longer than in classical t(15;17)(q24;q21). PCR analysis of the PML/RAR fusion gene according to standard protocols disclosed the presence of the L isoform. FISH studies using dual color dual fusion probes (Vysis) covering the entire PML and RARA genes , showed a classical 2F1G1R (2 fusion, 1 green, 1 red) signal pattern on nuclei. However , on metaphases, we detected a normal PML (red) and RARA (green) signals on normal chromosome 15 and 17 respectively , but the two fusion signals were located on der(17). The patient was treated with IC-APL protocols (all-trans retinoic acid plus daunorubicin) and complete remission was achieved after induction therapy. Discussion To explain the origin of the observed karyotype and molecular results, especially the double fusion signal on der(17), we propose two hypotheses: a classical t(15;17)(q24;q21) initially occurred leading to one fusion gene located on each derivative accompanied or followed either by a second translocation event implicating both derivative chromosomes with breakpoints located centromeric to the former breakpoint on der(15) and telomeric to the former breakpoint on der(17), or by an insertion of part of the der(15) containing the PML/RARA fusion gene into the der(17). Results obtained through FISH analysis support our first hypotheses. No differences in the clinical outcome between APL cases with classical t(15;17) and those with variant translocations leading to PML-RARA fusion gene have been reported. These results highlight the utility of combined cytogenetic, FISH and RT-PCR analyses to unveil the cases with variant or cryptic t(15;17). To our knowledge, this is the first report of an APL patient showing a variant t(15;17) involving only chromosomes 15 and 17 with two fusion signals on der(17). Disclosures: No relevant conflicts of interest to declare.

scholarly journals AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study

Blood ◽  
1996 ◽  
Vol 88 (4) ◽  
pp. 1390-1398 ◽  
Author(s):  
G Avvisati ◽  
F Lo Coco ◽  
D Diverio ◽  
M Falda ◽  
F Ferrara ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Pilot Study ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Massive Hemoptysis ◽  
Newly Diagnosed ◽  
Rt Pcr ◽  
Hybrid Gene ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

From March 1993 to October 1993, 20 consecutive, newly diagnosed acute promyelocytic leukemia (APL) patients from 13 Italian institutions entered in a pilot study named AIDA, combining all-trans retinoic acid (ATRA) with idarubicin (IDA). ATRA was administered orally beginning on the first day of induction at the dosage of 45 mg/m2/d until complete remission (CR), whereas IDA was administered intravenously at the dosage of 12 mg/m2/d on days 2, 4, 6, and 8 of the induction. Patients who achieved CR were consolidated with 3 courses of chemotherapy without ATRA; thereafter, they were followed up for molecular and hematologic CR. The median age was 35.3 years (range, 6.5 to 67.6 years); 8 patients were males and 12 females; 4 had the hypogranular variant of APL (M3v), and 4 (2 with M3v) presented with leukocyte counts > or = 10,000/microL. Molecular analysis for the promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) hybrid gene at diagnosis was performed in 16 patients by means of reverse transcription-polymerase chain reaction (RT-PCR) analysis, and all were RT-PCR+ for the hybrid gene. In the remaining 4 patients, the cytogenetic study showed the presence of the t(15;17). After a median time of 36 days (range, 28 to 52 days) 18 (90%) patients achieved CR; the remaining 2 patients died 12 and 34 days after diagnosis from myocardial infarction caused by fungal myocarditis and from massive hemoptysis, respectively. ATRA syndrome was observed in only 2 patients, and, after the prompt discontinuation of ATRA and initiation of dexamethasone, both recovered from the syndrome. However, after recovering, 1 patient achieved CR, whereas the other died at day 34 because of massive hemoptysis; other side effects were very limited. At recovery from the third consolidation course, only 3 of 14 (21.4%) tested patients were RT-PCR+ for the PML-RAR alpha hybrid gene. Of these, 2 relapsed shortly afterwards; however, in the last patient, the PML-RAR alpha disappeared at successive testing performed 2 months later. As of September 30, 1995, after a median follow-up period from diagnosis of 27 months (range, 24 to 31 months), the overall survival and event-free survival durations are 85% and 69%, respectively; moreover, 14 of 18 (78%) patients who achieved CR are still alive and in first molecular and hematologic CR. Of the 4 relapsed patients, 3 achieved a second CR with ATRA and, after further treatment, are now in molecular and hematologic CR after 4+, 16+, and 17+ months from the second CR. These results indicate that (1) the AIDA protocol is highly effective in treating APL; (2) after 3 consolidation courses, the majority of patients who achieved CR are RT-PCR- for the hybrid gene PML-RAR alpha; (3) the persistence of an RT-PCR positivity for the PML- RAR alpha hybrid gene after 3 consolidation courses is indicative of early relapse, thus these patients still require additional treatment. These results have prompted the Gruppo Italiano Malattie Ematologiche Maligne dell′Adulto (GIMEMA) to initiate, in cooperation with the Associazione Italiana di Ematologia ed Oncologia Pediatrica and some European Organization for Research and Treatment of Cancer (EORTC) centers, a new multicentric clinical trial named AIDA LAP 0493 for the treatment of adult and pediatric APL patients. All patients are considered eligible if APL diagnosis is confirmed with molecular or cytogenetic studies for PML-RAR alpha hybrid gene or t(15;17) and are enrolled to receive the same induction and consolidation therapy of this pilot study. After consolidation, patients who are RT-PCR- for PML- RAR alpha hybrid gene are randomized to four arms, whereas patients who are RT-PCR+ after consolidation undergo, if eligible, an allogenic transplantation procedure.

Experience with gemtuzumab ozogamycin (“mylotarg”) and all-trans retinoic acid in untreated acute promyelocytic leukemia

Blood ◽  
2002 ◽  
Vol 99 (11) ◽  
pp. 4222-4224 ◽  
Author(s):  
Elihu H. Estey ◽  
Francis J. Giles ◽  
Miloslav Beran ◽  
Susan O'Brien ◽  
Sherry A. Pierce ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Repeated Administration ◽  
Promyelocytic Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Polymerase Chain ◽  
Wbc Count ◽  
To Receive

We administered gemtuzumab ozogamycin (“mylotarg”; 9 mg/m2 day 1 or 5) and all-trans retinoic acid (ATRA) to 19 patients with untreated acute promyelocytic leukemia (APL). There were 3 patients who also received idarubicin because of a white blood cell (WBC) count of more than 30 000/μL. In complete remission (CR), patients were to receive 8 courses of mylotarg (9 mg/m2 every 4 to 5 weeks) and ATRA; idarubicin was added only for persistent or recurrent polymerase chain reaction (PCR) positivity. The CR rate was 16/19 (84%). All 12 patients tested to date were PCR-negative 2 to 4 months from CR date; none of the 7 patients evaluated subsequently have reverted to PCR positivity (median follow-up in CR was 5 months, up to 14 months). Mylotarg was well tolerated. A median of 5 post-CR courses have been given to date with 3 patients having currently received 8 post-CR courses, and 4 patients receiving 7 post-CR courses. Mylotarg appears active in APL, and repeated administration is feasible.

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