Outcome of pregnancy in women treated with all-trans retinoic acid; a case report and review of literature

All-trans-retinoic acid (ATRA) has been proved to be an effective treatment for acute promyelocytic leukemia (APL), inducing remission in more than 90% of cases. Treatment of APL in pregnancy is controversial as the use of ATRA has been questioned due to the teratogenic effect of retinoids. We report a case of pregnancy in a woman exposed to ATRA during the first trimester. The baby was born healthy, without any anomalies. Review of all reported cases of the use of ATRA in pregnancy revealed no serious adverse outcomes or congenital anomalies although only very few cases had exposure in the first trimester.     

Successful treatment of acute promyelocytic leukaemia during pregnancy

A case is reported of a pregnant 16-year-old-woman diagnosed with Acute promyelocytic leukaemia (APL) at 25 weeks gestation and treated with all-trans retinoic acid (ATRA) (45 mg/m2) for 25 days in combination with chemotherapy. She achieved a complete cytogenetic and molecular remission. Clinical course was complicated, with an intracerebral bleed, respiratory failure requiring ventilation and prolonged pancytopenia following initial chemotherapy. A live female infant was born at 28 weeks gestation who survived to discharge with significant pulmonary complications. She remains oxygen dependent at 6 months of age. ATRA has been used from the 3rd week of gestation, but fetal malformations are common during the first trimester. In contrast it seems to be safe in the second and third trimesters with regard to teratogenesis but can cause other side-effects. Most successful outcomes in treatment of APL during pregnancy are seen after treatment with ATRA and delivery of the baby at as late a stage as possible. Pregnancies terminated before remission has been obtained or those treated in the first trimester have a poor maternal outcome.     

Acute promyelocytic leukemia and pregnancy

In acute promyelocytic leukemia (APL), the use of all-trans-retinoic acid (ATRA) as a differentiating agent induces complete remission in a high percentage of patients. In pregnancy, however, this drug bears the risk of severe teratogenicity to the child. We report the case of a 23-yr-old woman at 21 weeks' gestation suffering from APL. She was treated with ATRA (45 mg/m2) for 40 d and two courses of standard chemotherapy. The mother achieved complete remission within 22 d of treatment. Fetal development was normal, and a healthy premature girl was born in the 35th week of pregnancy. In a review of the literature we have identified 14 cases of APL in pregnancy treated with ATRA alone or in combination with chemotherapy. ATRA has been used as early as in the 3rd week of gestation and in no case have malformations or other teratogenic effects occurred. Side-effects, however, ranged from fetal cardiac arrhythmias to induction of labour. Although known to exhibit severe teratogenic effects during the first trimester of pregnancy, ATRA seems to be reasonably safe during the second and third trimesters in the treatment of APL. However, careful obstetric follow-up is mandatory regarding fetal cardiac complications.     

Malignancy: Case Report: Acute Promyelocytic Leukemia in Late Pregnancy. Successful Treatment with All-Trans-Retinoic Acid (ATRA) and Chemotherapy

The use of all-transretinoic acid (ATRA) in APL is a great advance in the treatment of acute leukemia, driving the maturation steps until adult form. The effect of this medication in pregnant women with APL is being a safe and effective treatment only after the first trimester of pregnancy. If used in the first three months, it can cause fetus malformations due to its potent teratogenicity. The two patients we reported here, gave birth to normal children, yet they received ATRA. After a week with ATRA treatment, fibrinogen level improved and "D" dimers decreased, so as observed slowly maturation of leukemic leucocytes. ATRA used at the same time with chemotherapy; such as Cytarabine and Idarrubicine seems highly useful for induction and long term control of disease. One short discussion about the findings and compare with those found in the literature are presented.     

Long-term survival in an acute promyelocytic leukemia patient with recurrent granulocytic sarcomas: A case report

Rationale:Granulocytic sarcoma (GS) is an extramedullary myeloid tumor composed of immature cells of the granulocytic series. It rarely occurs in acute promyelocytic leukemia (APL). No case of long-term survival in an APL patient with recurrent GS has been reported.Patient concerns:A 54-year-old female patient was diagnosed with APL in 1995 and has been in complete remission (CR) of bone marrow morphology for 24 years; however, recurrent GS occurred successively in ovary, breast, spine, body of sternum, lymph nodes, soft tissues from 2004 to 2019.Diagnoses:The immunohistochemistry confirmed the diagnosis of GS, and fluorescence in situ hybridization (FISH) revealed its origin from APL.Interventions:She received surgery, and had an excellent response to all-trans retinoic acid (ATRA), DA (daunorubicin combined with cytarabine) regimens, and arsenic trioxide (ATO).Outcomes:The patient achieved CR in March 2020 after radiotherapy followed by ATO and ATRA. So far, she is still in follow-up.Lessons:It is rare that recurrent GS at multiple sites is involved in APL patient with bone marrow morphology in CR. It is interesting to observe a long-term excellent response to ATRA, chemotherapy and ATO. Although multiple recurrence of GS in patients with APL is rare, the data in this case highlight the need for individualized treatment when such conditions occur.     

All-trans retinoic acid and in vitro cytokine production by acute promyelocytic eukemia cells

Abstract: Leukemic cells spontaneously secrete cytokines involved in the proliferation of the clone; in this study we evaluated the effects of all-trans retinoic acid (ATRA) on the in vitro autocrine production of cytokines by acute myeloid leukemia cells. Thirty acute nonlymphoid leukemia cases (ANLL) (10 APL and 20 ANLL of other cytotypes than APL) were studied; the in vitro secretions of IL-1α, IL-3, IL-4, IL-6, IL-10, G–CSF, GM–CSF, TNF-α were tested with and without ATRA addition. After 5 d exposure to ATRA 10^?6 m APL-treated samples showed a significant reduction of IL-6 (p = 0.008) and GM–CSF (p = 0.03) and a significant increase of IL-1α (p = 0.01) production, if compared to untreated APL samples. No difference was seen in IL-3, IL-10 and IL-4 productions; G–CSF production resulted absent in all but 3 APL cases, in which addition of ATRA determined increase in the production. Interestingly, the 3 G–CSF-producing cases did not obtain clinical remission with ATRA; GM–CSF and IL-6 were spontaneously produced by all the cases, and 7 of 10 APL patients subsequently obtained complete remission after induction. TNF-α was produced only in 1 case. No statistical difference was seen in all the productions obtained from other than promyelocytic acute leukemic cells, both with and without ATRA addition. However, it is noteworthy that the production of IL-6 was more than twice as high in ANLL non-APL than in APL cases. In conclusion, these data could thus suggest possible complementary mechanisms of the exhaustion of the leukemic clone upon treatment with ATRA.     

Successful use of all-trans retinoic acid in acute promyelocytic leukaemia presenting during the second trimester of pregnancy

Summary. The development of acute leukaemia in pregnancy is a rare event, with an estimated incidence of 0·9–1·2 cases per 100 000 per year and with the majority of cases occurring in the second and third trimesters. We report a case of acute promyelocytic leukaemia (APL) developing during the second trimester of pregnancy which was successfully treated with all-trans retinoic acid (ATRA) resulting in a complete morphological remission.     

Acute promyelocytic leukemia with myelofibrosis: A case report and literature review

Rationale:Acute promyelocytic leukemia (APL) with myelofibrosis (MF) is rare, and only 14 cases have been reported in the literature to date.Patient concerns:A 42-year-old woman was admitted to the hospital with easy bruising and excessive bleeding. With the remission of the primary disease during treatment, the degree of fibrosis did not decrease, but worsened progressively.Diagnosis:The woman was diagnosed with acute promyelocytic leukemia with secondary myelofibrosis.Interventions:All-trans retinoic acid (ATRA) was discontinued after 6 months of complete remission of APL. Arsenic trioxide (ATO) was discontinued because of supraventricular tachycardia 9 months after complete remission of APL.Outcomes:After withdrawal of ATRA for 2 months, the degree of fibrosis was significantly alleviated, and after withdrawal of ATRA for 8 months and ATO for 5 months, bone marrow biopsy showed no reticular fiber deposition.Lessons:In this case report and review of an additional 14 cases of APL with MF, we highlighted the importance of the degree of MF to be evaluated by bone marrow biopsy at the time of bone marrow aspiration when APL is suspected. If MF is present, the type of MF should be determined in a timely manner, and appropriate intervention measures should be taken accordingly.     

How I treat children and adolescents with acute promyelocytic leukaemia

Acute promyelocytic leukaemia (APL) is a rare subtype of acute myeloid leukaemia. The outcome of paediatric APL has improved substantially over the past 20 years; cure rates above 80% are expected when all‐trans retinoic acid (ATRA) is given with anthracycline‐based regimens. The presenting features of paediatric APL may include severe bleeding and thrombotic complications, which contribute to the high early death rate. The incidence of leucocytosis and the microgranular subtype is greater in paediatric than adult APL, and children experience greater ATRA‐related toxicity. It is crucial to begin ATRA therapy and intensive platelet and fibrinogen replacement on first suspicion of APL. Recent risk‐adapted therapeutic trials have shown that patients at greater risk of relapse benefit from the introduction of high‐dose cytarabine during consolidation. Combination therapy with ATRA and arsenic trioxide provides very effective frontline treatment and may reduce the need for subsequent anthracycline therapy.     

Birth defects observed with maternal carbimazole treatment: Six cases reported to Nice's Pharmacovigilance Center

GoalsTo report cases of embryopathy occurring following first trimester exposure to anti-thyroid drugs.MethodsRetrospective screening of the database of our Pharmacovigilance Center from 1987 to date.ResultsWe report six cases of embryopathy, all following carbimazole exposure during the first trimester: two cases of abdominal wall defect, including one associated with facial dysmorphia; one case of digestive malformation (patent omphalomesenteric duct); two cases of aplasia cutis including one with facial dysmorphism; one case of bilateral choanal atresia with aorta coarctation associated with poorly controlled insulin dependent diabetes. Four out of five patients were euthyroid with treatment during the first trimester. We found a context suggesting genetic predisposition to congenital malformation in three cases: two cases of parental cleft lip/palate, one case of consanguinity. Outcome was favorable in all cases.ConclusionsWe want to raise awareness about the potential teratogenicity of carbimazole, probably on a predisposed genetic background. We suggest better reporting of congenital anomalies in children of women with Graves’disease, with or without in utero exposure to anti-thyroid drugs. In light of current literature, propylthiouracil should be the first line treatment for hyperthyroid women wishing a pregnancy.     

Genotypic and Phenotypic Characteristics of Acute Promyelocytic Leukemia Translocation Variants

Acute promyelocytic leukemia (APL) is a special disease entity of acute myeloid leukemia (AML). The clinical use of all-trans retinoic acid (ATRA) has transformed APL into the most curable form of AML. The majority of APL cases are characterized by the fusion gene PML-RARA. Although the PML-RARA fusion gene can be detected in almost all APL cases, translocation variants of APL have been reported. To date, this is the most comprehensive review of these translocations, discussing 15 different variants. Reviewed genes involved in APL variants include: ZBTB16, NPM, NuMA, STAT5b, PRKAR1A, FIP1L1, BCOR, NABP1, TBLR1, GTF2I, IRF2BP2, FNDC3B, ADAMDTS17, STAT3, and TFG. The genotypic and phenotypic features of APL translocations are summarized. All reported studies were either case reports or case series indicating the rarity of these entities and limiting the ability to drive conclusions regarding their characteristics. However, reported variants have shown variable clinical and morphological features, with diverse responsiveness to ATRA.     

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

Abstract

Background: The combination of all-trans-retinoic acid (ATRA) and chemotherapy has made acute promyelocytic leukemia (APL) a highly curable leukemia. However, several complications are reported with this treatment the most serious and life threatening being Retinoic Acid Syndrome (RAS). We aimed at identifying factors that could predict complications caused by ATRA during induction treatment of APL.

Patients: Forty-two patients with confirmed APL (by t(15;17) and/or PML/RARA) treated at our institution (University hospital of Tunis) between January 1998 and June 2006 using two consecutive protocols: European APL93 trial (24 patients) until February 2004 and Spanish PETHEMA LPA99 trial (18 patients) more recently. Induction regimen consisted of ATRA 45 mg/m²/d until CR combined to DNR 60 mg/m²/d×3+Cytarabine 200 mg/m²/d×7 (APL93) and Idarubicin 12 mg/m² d2, 4, 6, 8 (LPA99). Prednisone (0·5 mg/kg d1–d15) was added if WBC >10×10⁹/L to prevent RAS in LPA 99.

Results: Median age was 36 yr (7–64 yr), M/F=16/26 (0·61), median WBC was 2·4×10⁹/L (range 0·6–100×10⁹/L). WBC >10×10⁹/L was noted in 14 patients (33%). Additional cytogenetic abnormalities were seen in 12/42 (28%). Median body mass index (BMI=weight/height²:N 20–25) was 24 kg/m² (range 16–40 kg/m²), BMI >30 was noted in nine patients (8F and 1M). Thirty-three patients achieved CR (78·57%):18/24 (75%) in APL93 versus 15/18 (83%) in LPA99. Nine patients (21·42%) had early death. Causes of early death were: RAS (6) and CNS hemorrhage (3). Complications due to ATRA were: RAS (10), Scrotal ulcerations (3), Sweet syndrome (2), Perineal ulcerations (1), and Pseudotumor cerebri (1). Prognostic factors for complications of ATRA (Fisher exact test) were: BMI >35 (p=0·055), induction treatment without cytarabine (LPA99 trial) (p=0·047), whereas age (p=0·74), gender (p=0·51), initial WBC (p=0·47), and additional cytogenetic abnormalities (p=0·83) were not predictive. Retinoic Acid Syndrome was more reported in patients with initial WBC >10×10⁹/L (p=0·08).

Conclusion: We found high BMI (>35) in female and treatment without Cytarabine to increase the risk of developing complications with ATRA.     

Synergistic targeted therapy for acute promyelocytic leukaemia: a model of translational research in human cancer

Acute promyelocytic leukaemia (APL), the M3 subtype of acute myeloid leukaemia, was once a lethal disease, yet nowadays the majority of patients with APL can be successfully cured by molecularly targeted therapy. This dramatic improvement in the survival rate is an example of the advantage of modern medicine. APL is characterized by a balanced reciprocal chromosomal translocation fusing the promyelocytic leukaemia (PML) gene on chromosome 15 with the retinoic acid receptor α (RARα) gene on chromosome 17. It has been found that all‐trans‐retinoic acid (ATRA) or arsenic trioxide (ATO) alone exerts therapeutic effect on APL patients with the PML‐RARα fusion gene, and the combination of both drugs can act synergistically to further enhance the cure rate of the patients. Here, we provide an insight into the pathogenesis of APL and the mechanisms underlying the respective roles of ATRA and ATO. In addition, treatments that lead to more effective differentiation and apoptosis of APL cells, including leukaemia‐initiating cells, and more thorough eradication of the disease will be discussed. Moreover, as a model of translational research, the development of a cure for APL has followed a bidirectional approach of ‘bench to bedside’ and ‘bedside to bench’, which can serve as a valuable example for the diagnosis and treatment of other malignancies.     

Current standard treatment of adult acute promyelocytic leukaemia

The outcome of patients with acute promyelocytic leukaemia (APL) has dramatically improved over the last two decades, due to the introduction of combined all‐trans retinoic acid (ATRA) and chemotherapy regimens and, more recently, to the advent of arsenic trioxide (ATO). ATRA and anthracycline‐based chemotherapy remains a widely used strategy, providing cure rates above 80%, but it is associated with risk of severe infections and occurrence of secondary leukaemias. ATO is the most effective single agent in APL and, used alone or in combination with ATRA or ATRA and reduced‐intensity chemotherapy, results in greater efficacy with considerably less haematological toxicity. The toxic profile of ATO includes frequent, but manageable, QTc prolongation and increase of liver enzymes. Two large randomized studies have shown that ATRA + ATO is superior to ATRA + chemotherapy for newly diagnosed low‐risk APL resulting in 2–4 year event‐free survival rates above 90% and very few relapses. According to real world data, the spectacular progress in APL outcomes reported in clinical trials has not been paralleled by a significant improvement in early death rates, this remains the most challenging issue for the final cure of the disease.     

Treatment of acute promyelocytic leukemia with PETHEMA LPA 99 protocol: a Tunisian single center experience

Abstract

Acute promyelocytic leukemia (APL) has now become the most curable of all subtypes of acute myeloid leukemia. A cure rate of 75–80% can be anticipated with a combination of all-trans retinoic acid (ATRA) and anthracyclines. In Tunisia, the ATRA era began in 1998 with the use, consecutively, of two regimens of a combination of ATRA with anthracycline and cytarabine (APL93), and without cytarabine (LPA99). From 2004, 39 patients with confirmed APL either by t(15;17) or PML/RARA were treated by the PETHEMA LPA 99 trial. The rationale of this protocol by avoiding cytarabine is to reduce death in complete remission (CR) without increasing the incidence of relapse. Thirty-three patients achieved CR (84·6%). The remaining six patients were considered as failure due to early death: three caused by differentiation syndrome (DS) and three died from central nervous system hemorrhage. Baseline blood cell count (WBC) >10 × 10⁹/l (P=0·26) and creatinine >1·4 mg/dl (P=0·42) were not predictive of mortality. DS was observed in 11 patients (30·5%) with a median onset time of 12 days (range: 3–23 days) and median WBC of 29 × 10⁹/L (range: 1·2 × 10⁹–82·7 × 10⁹/l). DS was severe in seven cases, moderate in four, and fatal in three cases. Body mass index ≥30 (P=0·044) and baseline WBC ≥20 × 10⁹/l (P=0·025) are independent predictors of DS. The median follow-up of this study is 36 months. Thirty patients are alive in continuous complete remission; two patients died in CR from septic shock and secondary myelodysplastic syndrome respectively; one patient died 47 months after achieving two relapses. Event free survival from diagnosis was 80% and overall survival was 82%. Our results are quite acceptable and can be improved by reducing mortality rate.     

Relapsed/refractory acute promyelocytic leukemia with RARA-LBD region mutation was salvaged by venetoclax: A case report

Rationale:Acute promyelocytic leukemia (APL) is one of the most curable cancers. However, relapse of the disease is a difficult issue in clinical practice and it remains a great challenge that patients have a poor effect of conventional treatment in the clinic. Therefore, new and more effective therapeutic measures are urgently needed. Herein, we report a case of relapsed and refractory APL harboring a RARA-LBD region mutation successfully treated with venetoclax (VEN).Patient concerns:A 37-years-old woman was admitted to our hospital with worsening spontaneous gingival bleeding and skin ecchymosis. Physical examination revealed multiple petechiae and ecchymosis in the extremities.Diagnoses:The patient was diagnosed with L-type PML-RARα-positive APL, harboring a RARA-LBD region mutation, low-risk, based on bone marrow cytology, immunophenotypic analysis by flow cytometry, karyotype analysis, and molecular analysis.Interventions:Complete remission was achieved after the first induction therapy of all-trans retinoic acid (ATRA) combined with arsenic trioxide, but relapse was observed only after 11 months. Reinduction with ATRA and arsenic trioxide combined with anthracycline failed. Therefore, we tried to provide a new treatment with the Bcl-2 inhibitor VEN orally (100 mg d1, 200 mg d2 to d18, followed by 300 mg daily continuously).Outcomes:Clinical symptoms and laboratory indicators improved rapidly with VEN treatment. A complete hematologic response was achieved with VEN-based therapy.Lessons:Related drug resistance gene monitoring should be performed canonically in relapsed and refractory APL. Some relapsed and refractory APL that failed to respond to conventional treatment were at risk of death. Bcl-2 inhibitors are expected to be an effective salvage therapy for patients with resistance to ATRA, which is worthy of further discussion.     

Differentiation syndrome in acute promyelocytic leukaemia

Acute promyelocytic leukaemia differentiation syndrome (APL DS) is seen when patients with APL are treated with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). Presenting symptoms are varied but frequently include dyspnoea, unexplained fever, weight gain >5 kg, unexplained hypotension, acute renal failure and a chest radiograph demonstrating pulmonary infiltrates or pleural or pericardial effusion. Immediate treatment with steroids at the first clinical suspicion is recommended and ATRA/ATO should be stopped in severe cases or if there is no response to treatment. The utility of steroid prophylaxis in order to prevent APL DS is less certain. Here we provide a detailed review of the pathogenesis, clinical signs and symptoms as well as management and prophylaxis strategies of APL DS.     

Gastric emptying and orocecal transit time in pregnancy

Purpose. To evaluate the effects of pregnancy on gastrointestinal function, we determined gastric emptying time, orocecal transit time, and fasting gastrointestinal hormone levels (cholecystokinin, gastrin, pancreatic polypeptide, neurotensin) in 11 women with mild dyspeptic symptoms during the first and third trimesters of their pregnancies, and again 4–6 months after delivery. Methods. After the women ingested a disaccharide solution, orocecal transit time was determined by monitoring breath hydrogen concentrations at 10-min intervals, and values were compared with the postpartum value. Ultrasound examinations of gastric emptying were performed during the same intervals. Results. The half-emptying time and the final gastric emptying time did not differ in the first and third trimesters and postpartum, but gastrointestinal transit time was significantly longer in the third trimester of pregnancy than postpartum ([100.0 min (range, 50.5–240.0 min] vs 70.0 min [range, 40.5–240.0 min; P < 0.05]), respectively. Mean plasma pancreatic polypeptide values were lower in the third trimester of pregnancy than postpartum, and a negative correlation was observed between pancreatic polypeptide levels and transit time in the third trimester (r = −0.65; P = 0.0261). The plasma levels of other gastrointestinal hormones did not differ in the various periods studied. Conclusions. Our study shows that, despite evident dyspeptic symptoms, there were no significant alterations in gastric emptying or orocecal transit time during the first trimester of pregnancy. Conversely, in the third trimester, orocecal transit time was significantly longer. Received: October 6, 2000 / Accepted: February 23, 2001     

Improvement of prognosis in refractory and relapsed acute promyelocytic leukemia over recent years: the role of all-trans retinoic acid therapy

 With the aim of determining the ability of all-trans retinoic acid (ATRA) to improve prognosis in refractory and relapsed acute promyelocytic leukemia (APL), the data of 45 patients resistant to previous conventional chemotherapy or in first relapse were retrospectively reviewed. Thirty-seven patients presented with typical M3, five with variant form (M3v), and three with intermediate form. Seven patients died before any chemotherapy could be given. Thirty-five patients received one course of chemotherapy combining anthracyclines and cytarabine without (n=22) or with ATRA (n=13), according to different protocols. One elderly patient received only ATRA, and two patients received only low-dose cytarabine. Nine patients died within 4 weeks of relapse. A complete remission (CR) was achieved in 29 of the 38 patients retreated after first relapse or primary failure (76.3%, 95% CI: 60–89%). Among relapsed patients, four of five patients who had initially received ATRA therapy achieved a second CR when retreated by ATRA. The median second disease-free survival (DFS) was 23.3 months. Overall median survival was 7.8 months, with a 5-year survival rate of 29% (95% CI: 14–44%). Parameters found to be associated with decreased second CR rate were presence of hemorrhages and hemostatic disorder, and high levels of GGT at the time of relapse. Factors associated with short survival were WHO performance status >1, high serum LDH levels, and coagulopathy at time of relapse. Use of ATRA at time of relapse (n=14) was significantly associated with higher CR rates (p=0.008), longer DFS (median not reached versus 7.9 months;p=0.05), and longer survival after first relapse (median 32.3 months versus 4.4 months;p=0.003). In the multivariate analysis, the only factor predictive of poor prognosis for overall survival was the absence of ATRA therapy at relapse. We conclude that ATRA is effective in the treatment of relapsed or refractory APL and appears superior to chemotherapy alone. Received: 13 June 1997 / Accepted: 8 September 1997