CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS 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

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 x 10(9)/L had a better CR (85% v 62%, P =.0001) and reduced relapse risk (22% v 42%, 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 x 10(9)/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.

[1]  Thomas D. Schmittgen,et al.  Real-Time Quantitative PCR , 2002 .

[2]  C. Bloomfield,et al.  All-trans-Retinoic Acid in Acute Promyelocytic Leukemia , 2000 .

[3]  K. Tobal,et al.  RT-PCR method with increased sensitivity shows persistence of PML-RARA fusion transcripts in patients in long-term remission of APL , 1998, Leukemia.

[4]  F. Mandelli,et al.  Early Detection of Relapse by Prospective Reverse Transcriptase-Polymerase Chain Reaction Analysis of the PML/RARα Fusion Gene in Patients With Acute Promyelocytic Leukemia Enrolled in the GIMEMA-AIEOP Multicenter “AIDA” Trial , 1998 .

[5]  P. Fenaux,et al.  Retinoic Acid Syndrome , 1998, Drug safety.

[6]  Keith Wheatley,et al.  Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial , 1998, The Lancet.

[7]  D. Grimwade,et al.  Acute promyelocytic leukaemia with t(11;17)(q23;q12‐21) and a good initial response to prolonged ATRA and combination chemotherapy , 1998, British journal of haematology.

[8]  P. Freemont,et al.  Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia. , 1997, Blood.

[9]  A. Burnett,et al.  Lack of benefit of G-CSF on complete remission and possible increased relapse risk in AML: An MRC study of 800 patients [Abstract] , 1997 .

[10]  C. Bloomfield,et al.  Association of PML-RAR alpha fusion mRNA type with pretreatment hematologic characteristics but not treatment outcome in acute promyelocytic leukemia: an intergroup molecular study. , 1997, Blood.

[11]  T. Barbui,et al.  Molecular Remission in PML/RARα-Positive Acute Promyelocytic Leukemia by Combined All-trans Retinoic Acid and Idarubicin (AIDA) Therapy , 1997 .

[12]  M. Vignetti,et al.  Autologous Bone Marrow Transplantation for Acute Promyelocytic Leukemia in Second Remission: Prognostic Relevance of Pretransplant Minimal Residual Disease Assessment by Reverse-Transcription Polymerase Chain Reaction of the PML/RARα Fusion Gene , 1997 .

[13]  C. Bloomfield,et al.  Secondary cytogenetic changes in acute promyelocytic leukemia--prognostic importance in patients treated with chemotherapy alone and association with the intron 3 breakpoint of the PML gene: a Cancer and Leukemia Group B study. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  D. Sentero,et al.  Retinoic acid syndrome in acute promyelocytic leukemia. , 1997, Wisconsin medical journal.

[15]  R. Gray,et al.  Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council's 10th AML trial (MRC AML10). Adult and Childhood Leukaemia Working Parties of the Medical Research Council. , 1997, Blood.

[16]  D. Grimwade,et al.  Characterisation of the PML/RAR alpha rearrangement associated with t(15;17) acute promyelocytic leukaemia. , 1997, Current topics in microbiology and immunology.

[17]  D. Grimwade,et al.  Establishing the presence of the t( 15; 17) in suspected acute promyelocytic leukaemia: cytogenetic, molecular and PML immunofluorescence assessment of patients entered into the M.R.C. ATRA trial , 1996, British journal of haematology.

[18]  S. Langabeer,et al.  Minimal residual disease detection in acute promyelocytic leukemia by reverse-transcriptase PCR: evaluation of PML-RAR alpha and RAR alpha-PML assessment in patients who ultimately relapse. , 1996, Leukemia.

[19]  F. Mitelman ISCN 1995 : an international system for human cytogenetic nomenclature (1995) : recommendations of the International Standing Committee on Human Cytogenetic Nomenclature : Memphis, Tennessee, USA, October 9-13, 1994 , 1995 .

[20]  T. Naoe,et al.  Isoforms of PML-retinoic acid receptor alpha fused transcripts affect neither clinical features of acute promyelocytic leukemia nor prognosis after treatment with all-trans retinoic acid. The Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). , 1995, Leukemia.

[21]  J. Bennett,et al.  Characterization of acute promyelocytic leukemia cases with PML-RAR alpha break/fusion sites in PML exon 6: identification of a subgroup with decreased in vitro responsiveness to all-trans retinoic acid. , 1995, Blood.

[22]  L. Blaszkowsky,et al.  All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. , 1995, Blood.

[23]  K. Tobal,et al.  Persistence of RARa‐PML fusion mRNA detected by reverse transcriptase polymerase chain reaction in patients in long‐term remission of acute promyelocytic leukaemia , 1995 .

[24]  H. Dombret,et al.  All-trans-retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia. , 1995, Blood.

[25]  J. Wiley,et al.  Reduction of pulmonary toxicity by prednisolone prophylaxis during all-trans retinoic acid treatment of acute promyelocytic leukemia. Australian Leukaemia Study Group. , 1995, Leukemia.

[26]  T. Naoe,et al.  Prognostic significance of the RT-PCR assay of PML-RARA transcripts in acute promyelocytic leukemia. The Leukemia Study Group of the Ministry of Health and Welfare (Kouseisho). , 1995, Leukemia.

[27]  M. Tanimoto,et al.  All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. Japan Adult Leukemia Study Group. , 1995, Blood.

[28]  P. Maslak,et al.  Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid. , 1994, Blood.

[29]  E. Dmitrovsky,et al.  All-trans Retinoic Acid for Acute Promyelocytic Leukemia: Results of the New York Study , 1994, Annals of Internal Medicine.

[30]  P. Fenaux,et al.  Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group , 1993 .

[31]  T. Barbui,et al.  Molecular evaluation of residual disease as a predictor of relapse in acute promyelocytic leukaemia , 1992, The Lancet.

[32]  T. Lister,et al.  Diagnosis of acute promyelocytic leukaemia by RT‐PCR: detection of PML‐RARA and RARA‐PML fusion transcripts , 1992, British journal of haematology.

[33]  F. Lo Coco,et al.  Genomic variability and alternative splicing generate multiple PML/RAR alpha transcripts that encode aberrant PML proteins and PML/RAR alpha isoforms in acute promyelocytic leukaemia. , 1992, The EMBO journal.

[34]  E. Dmitrovsky,et al.  Reverse transcription polymerase chain reaction for the rearranged retinoic acid receptor alpha clarifies diagnosis and detects minimal residual disease in acute promyelocytic leukemia. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[35]  M. Tallman,et al.  Reassessing the hemostatic disorder associated with acute promyelocytic leukemia. , 1992, Blood.

[36]  E. Dmitrovsky,et al.  Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). , 1991, The New England journal of medicine.

[37]  R Berger,et al.  All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. , 1990, Blood.

[38]  T. Barbui,et al.  Early deaths and anti-hemorrhagic treatments in acute promyelocytic leukemia. A GIMEMA retrospective study in 268 consecutive patients. , 1990, Blood.

[39]  Zhen-yi Wang,et al.  Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. , 1988, Haematology and blood transfusion.

[40]  R. Gray,et al.  Comparison of 1 + 5 DAT and 3 + 10 DAT followed by COAP or MAZE consolidation therapy in the treatment of acute myeloid leukemia: MRC ninth AML trial. , 1987, Seminars in oncology.

[41]  K. McPherson,et al.  MORTALITY IN ORAL CONTRACEPTIVE USERS , 1981, The Lancet.

[42]  Iscn International System for Human Cytogenetic Nomenclature , 1978 .

[43]  J. Rowley,et al.  15/17 TRANSLOCATION, A CONSISTENT CHROMOSOMAL CHANGE IN ACUTE PROMYELOCYTIC LEUKAEMIA , 1977, The Lancet.

[44]  T. Sympson Lincoln County Hospital , 1864, British medical journal.

[45]  lhealtlhy youin-g,et al.  Hospital for Sick Children , 1857, British medical journal.