Management of Patient Primigravida 36-37 Weeks with Chronic Myeloid Leukemia, Anemia, and Thrombocytopenia: A Case Report

<p>Chronic myelogenous leukemia (CML) is a type of cancer caused by a disturbance in the hematopoietic stem cells. CML itself rarely occur on women who are in labor and an advanced procedure in this event has become a special challenge for medics, especially an anesthesiologist. This limits the development of standard anesthesia guidelines, so in this case we describe the incidence of CML in pregnancies performed by Cesarean section with general anesthesia.</p><p>The first pregnant patient was 36 weeks pregnant; the patient was first diagnosed with Chronic myelogenous leukemia (CML) at the age of 26-28 weeks, at that time the patient complained of frequent dizziness, abdominal pain and weakness, then the patient complained of bleeding gums, and currently the patient complained of nosebleeds. The Bone Marrow shows Conclusion an accelerated phase chronic myeloid leukemia (CML) (suspected atypical CML) with nutritional deficiency. We perform General Anesthesia technique Rapid Sequence Intubation with Regimen Fentanyl 100 mcg, Propofol 80 mg and Rocuronium 50 mg.</p><p>The patient was admitted to the ICU for 2 days before transferring to intensive care and the patient received intravenous paracetamol 1 gram four times, cefazolin 1 gram twice a day, lansoprazole 30 mg once a day, tranexamic acid 1gr three times a day, and 15 mcg per hour fentanyl contionously. Hemodynamic patients in the ICU are in a stable condition. On the second postoperative day of care, the patient was transferred to the High care ward, then at the third postoperative day the patient's hemodynamics was stable and the patient was transferred to a normal room.</p>

Current Treatments Do Not Improve the Prognosis of Patients with Atypical CML and Unclassified MDS/MPN. a Joint Report from Fi-LMC, FIM, Gfch and GFM

Background Atypical CML (aCML) is a rare myeloid neoplasm with molecular heterogeneity and overlapping features of MDS and MPN. Distinction from unclassified MDS/MPNu based on WHO criteria remains difficult, and the management of these closely related entities remains ill-codified. Most patients (pts) are managed with cytoreductive agents, but small series have reported responses to hypomethylating agents or tyrosine kinase inhibitors (TKI), notably ruxolitinib. Allogeneic stem cell transplantation (SCT) is considered the only curative option. To instruct clinical trials with novel agents in this rare and heterogeneous population, real-life cohorts must i) provide prognostic factors and molecular characterization able to stratify patients, and ii) benchmark outcomes with current treatment options. Methods The French National observational study of rare MDS/MPNs performed a retrospective analysis of adult patients with MDS/MPN from 35 centers. Cases were centrally reclassified according to the 2016 WHO criteria to exclude CMML, classical MPNs and CNL. All statistical analyses were done without dichotomizing continuous clinical or biological variables. The prognostic influence of treatments was analyzed considering onset of treatment as a time-dependent covariate (Mantel-Byar method). Results The study population included 136 pts (M/F 83/53), with a median age of 72 years. Only 43 (31.6%) met WHO 2016 criteria for aCML while the remaining 93 were classified as MDS/MPNu. At diagnosis, spleen enlargement or other tumor symptoms were present in 36% of pts, while 32% had constitutional symptoms. Mutations in ASXL1, splice genes (U2AF1, SF3B1, SRSF2 or ZRSR2), SETBP1, EZH2, CSF3R, JAK2 and ETNK1 were present in 68.8%, 50.0%, 30.3%, 15.9%, 12.7%, 12.6% and 7.4% of 63 tested cases, respectively. 25 pts had an AML transformation. With a median follow-up of 29.8 months (0.5-276.4) median overall survival (OS) and AML-free survival (AMLFS) were 25.6 and 20.6 months, resp. Median OS was 20.2 versus (vs) 29.7 months in aCML vs MDS/MPNu, resp (log rank test p=0.2) and median AMLFS was 16.6 vs 27.4 months, resp (p=0.09). In univariate analysis, higher WBC (p=0.003) and lower Hb level (p<10-5) predicted significantly shorter OS, while presence of splenomegaly or other tumor symptoms (p=0.08), higher proportion of IMC (p=0.06), lower platelet count (p=0.08) and dyserythropoieisis (p=0.05) tended to shorten OS. Age, gender, presence of constitutional symptoms, bone marrow or peripheral blast percentage or dysmegakaryopoiesis had no significant impact (all p>0.1). Patients with EZH2 mutations had shorter OS (median 9.9 vs 20.6 months in EZH2 wt pts, p=0.03), while other gene mutations had no significant prognostic impact (all p>0.1). All variables with p <0.1 in univariate analyses were included in a multivariate Cox model. After backward selection, only Hb levels (HR= 0.81, p<10-5) and dyserythropoiesis (HR=2.4, p=0.04) retained independent prognostic value. At any time during follow-up, 89 (65.4%) pts received cytoreductive agents (mostly hydroxyurea), while 23 (16.9%) received TKI (ruxolitinib in 12, imatinib in 8, dasatinib in 3 pts) and 18 (13.2%) HMA, resp. Of note, 8/18 pts received HMA at transformation to AML, while all pts received TKIs prior to AML. Finally, 19 pts (14.0%) received an SCT and 35.3% received ≥2 of the above-mentioned types of treatment. Median time to SCT, HMA and TKI were 10.2, 11.9 and 4.7 months, resp. In multivariate Cox models adjusting for baseline Hb level and dyserythropoieisis, neither cytoreduction (p=0.6) nor SCT (p=0.5) were associated with a significant OS improvement. Treatment with HMA was associated with a significantly worse OS (HR=3.0, p=0.001), but this effect was confounded when transformation to AML, as a time-dependent event, was included in the model (HMA: HR= 1.1, p=0.7, AML: HR=5.1, p<10-6). Finally, treatment with TKIs was also associated with significantly worse OS (HR=2.3, p=0.02). This TKI's detrimental effect was confirmed in a model also accounting for baseline WHO, (log-transformed) WBC count, platelet levels and bone marrow blast percentage. Conclusions Anemia and dyserythropoiesis are important prognostic factors in aCML and MDS/MPNu that should be used to stratify pts included in clinical trials. There is currently no standard of care for these overlap syndromes. Treatment with HMAs and TKIs should be restricted to clinical trials. Disclosures Rea: Incyte Biosciences: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Roy:Incyte Biosciences: Consultancy. Caers:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nicolini:Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Sun Pharma Ltd: Consultancy. Legros:Novartis: Honoraria; BMS: Honoraria; Incyte Biosciences: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

Decitabine (DAC) in Combination with Donor Lymphocyte Infusions (DLIs) Can Induce Remissions of Overt Aml Relapses after Allogeneic Transplantation

Background: Treatment with the DNA hypomethylating agents (HMAs) 5-azacytidine (AZA) or DAC has become a well-established option for elderly MDS and AML patients (pts). Regarding their mechanism of action, HMAs not only reactivate tumor suppressor genes, but also lead to an immune activation response, by expression of Cancer/testis antigens (Almstedt et al., Leuk. Res. 2010; Goodyear et al., Blood 2010) and endogenous retroviruses (Chiappinelli et al., Cell 2015; Roulois et al., Cell 2015). Hypothesizing that HMA-mediated immune activation may sensitize blasts to subsequent DLIs, we and others showed that AZA combined with DLIs can induce long-term remissions in pts with relapsed MDS/AML after allogeneic transplantation, particularly with a low leukemic burden, and after failure to respond to DLIs alone (Steinmann et al., BMT 2015, Schroeder et al., BBMT 2015). As DAC is considered useful also in pts with higher WBC and higher blast counts, we now treated 18 pts (most of them with more aggressive hematologic relapse) with DAC+DLIs. Patients and Methods: Between 10/06 and 03/16, 18 pts (median age 63 years, range 29-76, 10 males) with hematological relapse after allogeneic transplantation were treated with DAC and (where feasible) DLIs. Thirteen pts had AML (genetic risk by ELN: 3x int-1, 4x int-2, 6x adverse (4 MK+), 3 had MDS, 1 had polycythemia vera, 1 had atypical CML. Sixteen and 2 pts had received reduced-toxicity conditioning (mostly FBM) and myeloablative conditioning, respectively. Donors: matched unrelated in 8 pts, matched sibling in 4, mismatched in 6. DLIs at relapse after 1st/2nd transplant in 15/3 pts (1st/2nd/3rd/4th relapse in 11/5/1/1 pts). Median duration from transplant to hematologic relapse was 306 days (range, 56-4943). Median % blasts before DAC was 4% in peripheral blood (pb, range, 0-40%), 30 % in bone marrow (range, 7-60%), the median WBC was 4,770/µl (range, 430-30,800). DAC (20 mg/m2 per day) was administered either as a standard 5-day (15 pts) or a 10-day course (3 pts). DLIs were to be given 7 days after the last HMA dose. Prior AZA as relapse treatment was allowed. Results: Of 18 pts with myeloid neoplasias (mostly AML) with hematologic relapse after allografting, 15 received DAC+DLIs (for 8 of them after previous DLI-only, for 3 after previous AZA+DLI), 3 pts only received DAC (median number of DAC cycles: 2, range 1-8, median number of DLIs: 2, range 1-10). Two AML pts (aged 64 and 76 yr, no previous AZA, 7 and 4% pb blasts, respectively) attained a complete hematologic and molecular remission after 5-day DAC+DLI, with a duration of 250+ and 391 days, respectively. One of them is still in CR with no signs of GvHD, the other died in CR because of liver GvHD and hemosiderosis. A third AML pt attained complete donor chimerism following DAC+DLI but died at day 35 because of a fungal pneumonia (concurrent Sorafenib). Eleven additional pts achieved a temporary disease control (median duration 93 days, range 34-212), 5 of them were subsequently re-transplanted. Four pts showed no response to DAC+DLI, 3 developed GvHD. Seven pts died of PD, 6 pts of infections, 1 pt of intracranial hemorrhage, 1 pt of GvHD. Conclusions: DAC in combination with DLIs showed good feasibility in pts with relapsed AML/MDS after allogeneic transplantation. Despite overall higher median WBC and blast expansion than a large previous cohort treated with AZA+DLI, clinical activity was comparable, and in 2/18 pts (11%) a complete hematologic and molecular remission was achieved (despite the presence of peripheral blood blasts). This approach is investigated prospectively within the RELDAC substudy of the EORTC trial AML21 of older AML patients (inDACtion vs. induction, NCT02172872). Disclosures Claus: Janssen-Cilag: Consultancy, Honoraria, Other: Travel Funding; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Marks:Pfizer: Honoraria. Lübbert:Celgene: Other: Travel Funding; Ratiopharm: Other: Study drug valproic acid; Janssen-Cilag: Other: Travel Funding, Research Funding.

Increased Prevalence of t(8;9)(p21-23;p23-24) Translocations within 9p24 Abnormalities in Patients with Myeloid Malignancies Identified from the Mitelman Database

Background: Advances in detailing the interaction between tumor cells and host immune system has led to the potential of targeted immunotherapy. One target is the programmed death 1 (PD-1) pathway, which cancer cells up-regulate to evade T-cell-mediated immune response. Blockade of PD-L1 or PD-L2 has shown efficacy in solid tumors, as well as classic Hodgkin's lymphoma (cHL) and primary mediastinal b-cell lymphoma (PMBCL). In cHL and PMBCL, amplification or rearrangement of chromosome 9p24.1 is implicated in their pathogenesis. The genes PDL1 and PDL2 are located on 9p24.1, along with JAK2, which further induces PDL1 and PDL2. Targeted inhibitors of JAK2 are utilized in some myeloid malignancies (MM), mostly as gain of function point mutations. The aim of this study is to determine the prevalence of and classify 9p24.1abnormalities across subtypes of MM to guide future studies for targeted therapy. Methods: A service of the National Cancer Institute, theMitelman Database of Chromosome Aberrations and Gene Fusions in Cancer database is manually updated from the literature and organized into three sub-databases: cases of chromosomal aberrations, molecular biology and clinical associations, and references. We searched for the 9p24 breakpoint within hematologic malignancies with no other search limits and subsequently divided the cases into myeloid and lymphoid subtypes. The incidence of rearrangements and additions in chromosome 9p24 for myeloid subtypes were determined. Those with either incidence >0.5% ort(8;9)(p21-23;p23-24) translocations are reported. Results: 9p24 alterations occurred in 92 of 25,284 cases (<0.4%) of MM across 24 subtypes, with 22 (<0.1%) of these additions. Of subtypes with at least 100 cases, 9p24 alterations in chronic myeloproliferative disorder, NOS (7/326, 2.1%) and idiopathic myelofibrosis (3/311, 1.0%) were the most common. Chronic myeloid leukemia (CML),t(9;22),myelodysplastic syndrome and acute myeloid leukemia (aml) had <1% incidence of 9p24 rearrangements and additions. Myelodysplastic/myeloproliferative disease, NOS (5/61, 8.2%), atypical CML (4/61, 6.6%) and chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (4/65, 6.2%) contained the most frequent 9p24 alterations. Notably,t(8;9)(p21-23;p23-24) translocations accounted for 21/92 (22.8%) MM 9p24 alterations and were seen in 8 subtypes:myelodysplastic/myeloproliferative disease, NOS (5 cases), CEL/hypereosinophilic syndrome (4), atypical CML (3), chronic myeloproliferative disorder, NOS (3), aml-m1 (2), aml-m2 (2), aml-m6 (1), and idiopathic myelofibrosis (1). One patient with aml-1 and one with chronic myeloproliferative disorder was found with t(9;22)(p24;q11). Conclusions: Despite a low incidence of 9p24 rearrangements and additions across all MM within the Mitelman database, t(8;9)(p21-23;p23-24) translocations were seen in 8 MM subtypes and accounted for 22.8% of observed alterations. This translocation results in the fusion of PCM1-JAK2, leading to activation of Janus Kinase 2. Other than two patients with t(9;22)(p24;q11), harboring fusion of BCR-JAK2,no other rearrangements involving JAK2 were identified.While the use of JAK2 inhibitorruxolitinib has been described in 3 patients with t(8;9)(p21-23;p23-24), 2 with chronic eosinophilic leukemia and 1 with myeloproliferative disease, other MM subtypes with this translocation have not been evaluated. Further, no study has assessed such cases with FISH and other testing to streamline potential forPD-L1 or PD-L2 inhibitors. This data supports the utility of theMitelman database to identify alterations that can be further evaluated for targeted therapy and clinical trials. Disclosures No relevant conflicts of interest to declare.