163. Remission induction therapy of refractory acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA)

SummaryHemostatic molecular markers were serially monitored in a prospective fashion during remission induction therapy with all-trans retinoic acid (ATRA) in sixteen patients with acute promyelocytic leukemia (APL). One patient with leukocytosis before treatment and three patients who later developed hyperleukocytosis also received chemotherapy with behenoyl Ara-C and daunorubicin. Plasma levels of E-fragment of fibrin and fibrinogen degradation product (FDP-E), FDP-D dimer (D-D), thrombin-antithrombin complex (TAT), and plasmin-α2 plasmin inhibitor complex (PIC) were markedly elevated in all but one patient before treatment, and these parameters decreased to normal or near normal ranges in most patients within the first 7 days of treatment. Interestingly, we have found that these parameters were again elevated during the later course of ATRA therapy (after day +7) in eleven patients for various reasons including cytotoxic chemotherapy (3 cases), fever (5 cases; 2 cases with apparent infection, 3 cases without known etiology), Caesarean section (1 case), and no apparent etiology (2 cases). Three patients showed bleeding complications during reelevation of molecular markers, but none developed thrombosis. Plasma elastase-α1 proteinase inhibitor complex (E-α1PI) was markedly elevated in all patients at diagnosis and did not decrease significantly during ATRA therapy. Plasma tissue factor antigen was mildly elevated in one out of four patients studied, and thrombomodulin was elevated in two out of ten patients tested. These results confirmed the rapid normalization of coagulopathy during the early phase of remission induction therapy with ATRA but suggest that re-elevation of molecular markers occurs frequently during the later course of ATRA therapy.

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Reversible cardiac dysfunction without myocytolysis related to all-trans retinoic acid administration during induction therapy of acute promyelocytic leukemia

Annals of Hematology ◽

10.1007/s00277-008-0552-2 ◽

2008 ◽

Vol 88 (1) ◽

pp. 91-92 ◽

Cited By ~ 6

Author(s):

Annunziata Manna ◽

Luigi Cadenotti ◽

Andrea Motto ◽

Piercarlo Ballo

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Induction Therapy ◽

Cardiac Dysfunction ◽

Promyelocytic Leukemia ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Acid Administration

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All-trans-retinoic acid–induced pseudotumor cerebri in acute promyelocytic leukemia

Journal of Neurosciences in Rural Practice ◽

10.1055/s-0039-1700329 ◽

2014 ◽

Vol 05 (03) ◽

pp. 273-275

Author(s):

T. M. Anoop ◽

Nidhi Jain ◽

Sreejith G. Nair ◽

Geetha Narayanan

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Induction Therapy ◽

Treatment Strategy ◽

Pseudotumor Cerebri ◽

Promyelocytic Leukemia ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

ABSTRACTAll-trans-retinoic acid is an integral part in the treatment strategy of acute promyelocytic leukemia (APL). Here we describe a case of pseudotumor cerebri associated with all-trans-retinoic acid (ATRA) during the induction therapy in an adult with acute promyelocytic leukemia (APL).

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Resistance to all-trans retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukemia: study of in vitro ATRA sensitivity and cellular retinoic acid binding protein levels in leukemic cells [see comments]

Blood ◽

10.1182/blood.v82.7.2175.2175 ◽

1993 ◽

Vol 82 (7) ◽

pp. 2175-2181 ◽

Cited By ~ 127

Author(s):

L Delva ◽

M Cornic ◽

N Balitrand ◽

F Guidez ◽

JM Miclea ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Induction Therapy ◽

Binding Protein ◽

Promyelocytic Leukemia ◽

Leukemic Cells ◽

Differentiation Induction ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract All-trans retinoic acid (ATRA) induces leukemic cell differentiation and complete remission (CR) in a high proportion of patients with acute promyelocytic leukemia (AML3 subtype). However, relapses occur when ATRA is prescribed as maintenance therapy, and resistance to a second ATRA-induction therapy is frequently observed. An induced hypercatabolism of ATRA has been suggested as a possible mechanism leading to reduced ATRA sensitivity and resistance. CRABPII, an RA cytoplasmic binding protein linked to RA's metabolization pathway, is induced by ATRA in different cell systems. To investigate whether specific features of the AML3 cells at relapse could explain the in vivo resistance observed, we studied the CRABP levels and in vitro sensitivity to ATRA of AML3 cells before and at relapse from ATRA. Relapse-AML3 cells (n = 12) showed reduced differentiation induction when compared with “virgin”-AML3 cells (n = 31; P < .05). Dose-response studies were performed in 2 cases at relapse and showed decreased sensitivity to low ATRA concentrations. CRABPII levels and in vitro differentiation characteristics of AML3 cells before and at relapse from ATRA therapy were studied concomittantly in 4 patients. High levels of CRABPII (median, 20 fmol/mg of protein) were detected in the cells of the 4 patients at relapse but were not detected before ATRA therapy. Three of these patients showed a decrease in differentiation induction of their leukemic cells, and a failure to achieve CR with a second induction therapy of ATRA 45 mg/m2/day was noted in all patients treated (n = 3). Results from this study provide evidence to support the hypothesis of induced-ATRA metabolism as one of the major mechanisms responsible for ATRA resistance. Monitoring CRABPII levels after ATRA withdrawal may help to determine when to administer ATRA in the maintenance or relapse therapy of AML3 patients.

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Intensive chemotherapy(CT) after remission induction with all-trans-retinoic acid (ATRA) in acute promyelocytic leukemia (APL)

European Journal of Cancer ◽

10.1016/0959-8049(93)91452-q ◽

1993 ◽

Vol 29 ◽

pp. S150

Author(s):

AB Sousa ◽

JP Femandes ◽

V Mesquita ◽

G Ferreira ◽

P Ribeiro ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Remission Induction ◽

Intensive Chemotherapy ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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Predictive factors of all-trans-retinoic acid related complications during induction therapy for acute promyelocytic leukemia

Hematology ◽

10.1179/102453308x316112 ◽

2008 ◽

Vol 13 (3) ◽

pp. 142-146 ◽

Cited By ~ 20

Author(s):

Ramzi Jeddi ◽

Karima Kacem ◽

Hend Ben Neji ◽

Samia Mnif ◽

Emna Gouider ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Induction Therapy ◽

Predictive Factors ◽

Promyelocytic Leukemia ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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Successful remission induction by low-dose all-trans retinoic acid alone in a patient with acute promyelocytic leukemia and renal impairment

Leukemia Research ◽

10.1016/j.leukres.2007.05.005 ◽

2008 ◽

Vol 32 (3) ◽

pp. 512-514 ◽

Cited By ~ 1

Author(s):

Kengo Matsumoto ◽

Hiroya Tamaki ◽

Tamotsu Yamagami ◽

Noriaki Sasaki ◽

Shuuji Hara ◽

...

Keyword(s):

Retinoic Acid ◽

Renal Impairment ◽

Acute Promyelocytic Leukemia ◽

Low Dose ◽

Promyelocytic Leukemia ◽

Remission Induction ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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Molecular Remissions Induced by Liposomal-Encapsulated All-Trans Retinoic Acid in Newly Diagnosed Acute Promyelocytic Leukemia

Blood ◽

10.1182/blood.v94.7.2230.419k05_2230_2235 ◽

1999 ◽

Vol 94 (7) ◽

pp. 2230-2235 ◽

Cited By ~ 76

Author(s):

Elihu H. Estey ◽

Francis J. Giles ◽

Hagop Kantarjian ◽

Susan O’Brien ◽

Jorge Cortes ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Effective Means ◽

Promyelocytic Leukemia ◽

Remission Induction ◽

Newly Diagnosed ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Wbc Count

All-trans retinoic acid administered orally (oral ATRA) may not regularly lead to either molecular complete remissions (CRs) or prolonged hematologic CRs (HCR) unless combined with chemotherapy. Because serum tretinoin concentrations are higher, and maintained longer, after use of liposomal-encapsulated ATRA (lipoATRA) rather than oral ATRA, we investigated lipoATRA monotherapy in newly diagnosed acute promyelocytic leukemia (APL). Patients received lipoATRA 90 mg/m2 every other day for remission induction. The same dose was given 3 times a week until 9 months had elapsed from HCR date. Treatment then stopped. Chemotherapy (idarubicin 12 mg/m2daily days 1-2 for 2 courses) was to be added only if 2 polymerase chain reaction (PCR) tests, performed 2 weeks apart, were positive at 3, 6, or 9 months from HCR date. The sensitivity level of the PCR was 10−4. We treated 18 patients (median age, 54 years; median white blood cell [WBC] count 4,500/μL). The HCR rate was 12/18 (67%, 95% confidence interval [CI], 41% to 87%). This rate was similar to that we observed in a previous study using oral ATRA + idarubicin. Nine of 10 patients studied at HCR date were PCR-positive. Subsequently, however, overall (+/− idarubicin) rates of PCR positivity were 0/12 at 3 months, 1/10 at 6 months, 1/7 at 9 and 12 months, and 0/4 at 15 to 17 months. Idarubicin has been added in 3 patients, with this addition occurring at 6 months in 2 patients and at 9 months in 1 patient. Among patients who had not received idarubicin when the PCR was evaluated, 0 of 12 were PCR-positive at 3 months, 1 of 10 was positive at 6 months, 1 of 6 was positive at 9 months, 0 of 4 were positive at 12 months, and 0 of 3 were positive at 15 to 17 months. Morphologic APL has recurred in 1 patient, with a median follow-up time of 13 months in the 11 patients remaining in first CR. The median follow-up time is 9½ months (range, 3 to 17) in the 9 patients who have received only lipoATRA and who remain PCR-negative and in first CR. Our data suggest that lipoATRA is an effective means of producing molecular CR in newly diagnosed APL.

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