The occurrence of chronic myeloid leukemia in pregnancy is rare and its management poses a clinical challenge for physicians treating these patients. We report a 30-year-old woman with chronic myeloid leukemia who became pregnant twice successfully. Philadelphia-positive CML in its chronic phase was diagnosed at 16 weeks of her first gestation. At that time, she received no treatment throughout her pregnancy. At 38 weeks of gestation, a normal infant was delivered by cesarean section. At six weeks postpartum, the patient underwent imatinib mesylate therapy but she could not tolerate the treatment. The treatment was then changed to nilotinib at 400 mg orally b.i.d. Two years later, she became pregnant again while she was on nilotinib 200 mg b.i.d. The unplanned pregnancy was identified during her 7.4 weeks of gestation. Because the patient elected to continue her pregnancy, nilotinib was stopped immediately, and no further treatment was given until delivery. Neither obstetrical complications nor structural malformations in neonates in both pregnancies were observed. Both babies' growth and development have been normal. Although this experience is limited to a single patient, the success of this patient demonstrates that the management of chronic myeloid leukemia in pregnant women may be individualized based on the relative risks and benefits of the patient and fetus.

Here we report the case of an 18-year-old woman with chronic myeloid leukemia (CML) who became pregnant while undergoing treatment with dasatinib. Before pregnancy, she received imatinib mesylate therapy but could not tolerate the treatment. The regimen was then changed to dasatinib at a dose of 70 mg b.i.d. While she was in hematological remission and on dasatinib therapy, she became pregnant. The unplanned pregnancy was identified after the patient had experienced four weeks of amenorrhea. Because the patient elected to continue the pregnancy to term, dasatinib was stopped immediately. Meanwhile, CML hematological relapse occurred and then she was treated with interferon-α (IFN-α) (9 million IU/day) throughout the pregnancy without a complete hematological response. She successfully gave birth to a male baby at 33 weeks by cesarean section delivery with no sequelae or malformations. Although this experience is limited to a single patient, it provides a useful contribution for counselling patients inadvertently exposed to dasatinib during pregnancy.

BackgroundThe monitoring of BCR-ABL transcript levels by real-time quantitative polymerase chain reaction (RT-qPCR) has become important to assess minimal residual disease (MRD) and standard of care in the treatment of chronic myeloid leukemia (CML). In this study, we performed a prospective, sequential analysis using RT-qPCR monitoring of BCR-ABL gene rearrangements in blood samples from 91 CML patients in chronic phase (CP) who achieved complete cytogenetic remission (CCyR) and major molecular remission (MMR) throughout imatinib treatment.MethodsThe absolute level of BCR-ABL transcript from peripheral blood was serially measured every 4 to 12 weeks by RT-qPCR. Only level variations > 0.5%, according to the international scale, was considered positive. Sequential cytogenetic analysis was also performed in bone marrow samples from all patients using standard protocols.ResultsBased on sequential analysis of BCR-ABL transcripts, the 91 patients were divided into three categories: (A) 57 (62.6%) had no variation on sequential analysis; (B) 30 (32.9%) had a single positive variation result obtained in a single sample; and (C) 4 (4.39%) had variations of BCR-ABL transcripts in at least two consecutive samples. Of the 34 patients who had elevated levels of transcripts (group B and C), 19 (55.8%) had a < 1% of BCR-ABL/BCR ratio, 13 (38.2%) patients had a 1% to 10% increase and 2 patients had a >10% increase of RT-qPCR. The last two patients had lost a CCyR, and none of them showed mutations in the ABL gene. Transient cytogenetic alterations in Ph-negative cells were observed in five (5.5%) patients, and none of whom lost CCyR.ConclusionsDespite an increase levels of BCR-ABL/BCR ratio variations by RT-qPCR, the majority of CML patients with MMR remained in CCyR. Thus, such single variations should neither be considered predictive of subsequent failure and nor an indication for altering imatinib dose or switching to second generation therapy. Changing of imatinib on the basis of BCR-ABL/BCR% sustained increase and mutational studies is a prudent approach for preserving other therapeutic options in imatinib-resistant patients.

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Imatinib Mesylate (Gleevec™ or Glivec™ from NOVARTIS) is widely used for the treatment of CML inhibiting the BCR-ABL tyrosine kinase activity. Although, 90% of the patients respond to this treatment, resistance to this drug has been seen, mainly due mutations in the tyrosine kinase domain of BCR-ABL. Recently, has been reported that imatinib is a substrate for the ABC-transporters BCRP (breast cancer resistance protein) and MDR1 (P-Glycoprotein). Based in that report, we examined the expression of those two ABC-transporter, by quantitative PCR (Q-PCR) technology, in 29 CML patients who were resistant to IM (9 CP, 17 AP, and 3 BC), in 34 untreated CML patients (23 CP, 10 AP, and 1 BC) and 6 normal blood donors. cDNA was synthesized for RQ-PCR, which was performed on peripheral blood samples drawn after loss of CHR or MCyR for those with resistance to imatinib and prior to start of treatment with imatinib and those untreated patients. All samples were analyzed using SYBER Green technology and reported as the 2−Δ Δ Ct where it assumes that the amplification efficiency of the target gene (BCRP or MDR1) and the internal control gene (ABL) are the same. Resistant patients had a significantly higher levels of BCRP expression than untreated patients, and normal blood donors with a median ratio of 2.1 (range, 0.04–34.2) vs. 0.64 (range, 0–18.6) vs. 0.6 (range, 0.07–1.41) (Wilcoxon test, P<0.0002). For the MDR1 gene expression, patients with resistance to imatinib had also a significantly higher level, median ratio of 1.65 (range, 0.09–10.8) vs. 0.68 (range, 0.01–2.63) in untreated patients and normal blood donors median ratio 0.76 (range, 0.02–1.92) (P < 0.0017). Nineteen of 29 resistant patients (65.5%) overexpressed BCRP and 41.3% (12/29) overexpressed MDR1, meantime only 26.5% (9/34) and 11.8% (4/34) of the untreated CML patients overexpressed BCRP and MDR1 respectively (X2 test P=0.004 and P=0,022). Overexpression of BCRP was more frequent in AP of the resistant group (70%) than the untreated patients (30%) (Fisher exact test P=0.05). When comparing the expression of MDR1 between the resitant group in AP (35,3%) and the untreated one in the same phase (40%) no statistic difference was seen (P=1). Patients in CP and BC do not show any difference in the expression of BCRP and MDR1 regardless the presence or not of resistance to imatinib. These data confirms that high expression of BCRP or MDR1 may contribute to imatinib resistance phenotype leading to a reduction in intracellular imatinib concentrations.Further follow-up is necessary for those untreated CML patients that overexpress, at diagnosis, those ABC-transporters BCRP and MDR1. These may reveal correlations between the expression and clinical prognosis and may allow the development of new starategies to overcome imatinib mesylate resistance.