Outcome of CML patients with de novo bleeding complications: Do they behave differently?

e18546 Background: Chronic myeloid leukemia (CML) is a clonal hematopoietic neoplasm. A subset of CML patients present may present with unusual bleeding manifestations. There is limited data on the incidence and outcome of such patients on treatment with imatinib. Methods: We analysed the CML patients treated at PGIMER Chandigarh from January 2003 to December 2018. Baseline spleen and liver size, hematological parameters, Sokal and Hasford score, site and severity of bleeding (as per WHO classification) were recorded. The treatment response, occurrence of cytopenias and need for second line TKI were analyzed. Results: Sixty-six patients (2.8%) out of 2350 adult CML patients had bleeding at diagnosis. The median age was 35 years (range 15 – 66 years); 56.1% were males. The median duration of follow up was 79 months (range 6 – 123 months). Splenomegaly and hepatomegaly was found in 89.3% and 65.1% patients, respectively. Baseline median hemoglobin was 9.5 g/dL; TLC was 151600/mm3 and platelet count was 301000/mm3. Based on Sokal score, 15/66, 26/66 and 25/66 patients belonged to low, intermediate and high risk categories, respectively. According to Hasford score, 22/66, 36/66 and 8/66 patients belonged to low, intermediate and high risk categories, respectively. Based on WHO grading, 33/66, 30/66 and 3/66 patients had grade 1, 2 and 3 bleed, respectively. 48 patients had mucocutaneous bleeding [cutaneous 17, gum bleed 16, epistaxis 15], 4 had psoas haematoma, 7 had vaginal bleeding, 3 had ocular bleeding, 6 had GI bleed [upper GI 3, lower GI 3], 3 had hematuria. 74.2% achieved CHR at 6 weeks and 83.3% achieved MMR at 12 months with Imatinib. 18 developed cytopenias which required Imatinib interruption or dose reduction. 18 required Imatinib dose escalation for suboptimal response, 5 patients received second line TKI. Six patients progressed to advanced phase CML (AP/BC) after a median duration of 32 months (range 21 – 49 months). Bleeding manifestations resolved in all patients and there was no recurrence of bleeding on follow up. Conclusions: Bleeding is an uncommon presentation of CML. It might be a harbinger of an increased risk of cytopenias, suboptimal treatment response and disease progression on Imatinib.

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CML patients presenting with priapism: Is there any disparity in outcome?

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e18545 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e18545-e18545 ◽

Cited By ~ 1

Author(s):

Aditya Jandial ◽

Kundan Mishra ◽

Rajeev Sandal ◽

Deepesh Lad ◽

Gaurav Prakash ◽

...

Keyword(s):

High Risk ◽

Developing World ◽

Study Cohort ◽

Age Group ◽

Shunt Surgery ◽

Duration Of Symptoms ◽

Ischemic Priapism ◽

Hasford Score ◽

Risk Categories

e18545 Background: Priapism, a urological emergency that needs prompt treatment, is an uncommon presenting feature of chronic myeloid leukemia (CML). CML frequently occurs in younger males and adolescents in developing countries. Occurrence of erectile dysfunction (ED) in this particular age group can severely decrease the quality of life. It is known that immediate treatment of priapism preserves erectile function. The data on the outcome of priapism in CML patients from developing world is limited. Methods: We analysed the CML patients treated at PGIMER Chandigarh from January 2003 to December 2018. Baseline spleen and liver size, hematological parameters, Sokal and Hasford score were documented. Duration of priapism, treatment received by the patients, and response to Imatinib were recorded. The severity of ED was assessed by SHIM (Sexual Health Inventory for Men) score. Results: Twenty-three patients (1.7%) out of total 1350 male CML-CP patients had priapism at diagnosis. The median age was 24 years (range 13 – 50 years); 60.8% patients belonged to 21 – 40 years age group. Median duration of priapism was 8 days (range 2 – 25 days). Splenomegaly and hepatomegaly were found in 91.3% and 56.5% patients, respectively. Baseline median hemoglobin was 9.9 g/dL; TLC was 283000/mm3 and platelet count was 352000/mm3. Based on Sokal score, 4/23, 16/23 and 3/23 patients belonged to low, intermediate and high risk categories, respectively. According to Hasford score, 7/23, 14/23 and 2/23 patients belonged to low, intermediate and high risk categories, respectively. All patients received cytoreductive therapy [hydroxyurea and Imatinib]; 21 patients underwent penile aspiration, 13 patients underwent therapeutic leucapheresis and 8 patients underwent distal penile shunt surgery. Majority of the patients (78.2%) achieved CHR at 6 weeks and 21 patients achieved MMR at 12 months. ED could be assessed in 14 patients on follow up. As per SHIM score, 2/14 and 12/14 patients had moderate and severe ED, respectively. The occurrence and severity of ED was unaffected by leucapheresis or shunt surgery. Conclusions: We found severe ED on follow up among majority of CML-CP patients with priapism at presentation. Despite favourable response to Imatinib, long duration of symptoms and hyperleucocytosis probably contributed to ischemic priapism and severe ED in the study cohort. We conclude that prolonged and untreated priapism in CML-CP patients is a major risk factor for ED. There is a need to sensitise the primary care physicians and surgeons in the developing world regarding this grave complication in CML patients.

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Anomalous origin of the right coronary artery with interarterial course: a mid-term follow-up of 28 cases

Scientific Reports ◽

10.1038/s41598-021-97917-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Francisco Albuquerque ◽

Pedro de Araújo Gonçalves ◽

Hugo Marques ◽

António Ferreira ◽

Pedro Freitas ◽

...

Keyword(s):

Coronary Artery ◽

High Risk ◽

Right Coronary Artery ◽

Cardiac Death ◽

Anomalous Origin ◽

Cardiac Symptoms ◽

Asymptomatic Patients ◽

Increased Risk ◽

The Right

AbstractAnomalous origin of the right coronary artery from the opposite sinus (right-ACAOS) with interarterial course (IAC) has been associated with increased risk of sudden cardiac death (SCD). Widespread use of coronary computed tomography angiography (CCTA) has led to increased recognition of this condition, even among healthy individuals. Our study sought to examine the prevalence, anatomical characteristics, and outcomes of right-ACAOS with IAC in patients undergoing CCTA for suspected coronary artery disease (CAD). We conducted a retrospective analysis of consecutive patients referred for CCTA at one tertiary hospital from January 2012 to December 2020. Patients exhibiting right-ACAOS with IAC were analyzed for cardiac symptoms and mid-term occurrence of first MACE (cardiac death, SCD, non-fatal myocardial infarction (MI) or revascularization of the anomalous vessel). CCTAs were reviewed for anatomical high-risk features and concomitant CAD. Among 10,928 patients referred for CCTA, 28 patients with right-ACAOS with IAC were identified. Mean age was 55 ± 17 years, 64% were male and 11 (39.3%) presented stable cardiac symptoms. Most patients had at least one high risk anatomical feature. During follow-up, there were no cardiac deaths or aborted SCD episodes and only 1 patient underwent surgical revascularization of the anomalous vessel. Right-ACAOS with IAC is an uncommon finding (prevalence of 0.26%). In a contemporary population of predominantly asymptomatic patients who survived this condition well into adulthood, most patients were managed conservatively with a low event rate. Additional studies are needed to support medical follow-up as the preferred option in this setting.

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Abstract 13943: Hypertrophic Cardiomyopathy with Left Ventricular Apical Aneurysm Represents a High-Risk Subgroup Necessitating Aggressive Preventive Therapy: A Long-term Follow-Up Study

Circulation ◽

10.1161/circ.130.suppl_2.13943 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Ethan J Rowin ◽

Barry J Maron ◽

Tammy S Haas ◽

John R Lesser ◽

Mark S Link ◽

...

Keyword(s):

Heart Failure ◽

Hypertrophic Cardiomyopathy ◽

High Risk ◽

Sudden Death ◽

Left Ventricular ◽

Increased Risk ◽

Long Term Follow Up ◽

Apical Aneurysm

Background: Increasing penetration of high spatial resolution cardiovascular magnetic resonance (CMR) imaging into routine cardiovascular practice has resulted in more frequent identification of a subset of hypertrophic cardiomyopathy (HCM) patients with thin-walled, scarred left ventricular (LV) apical aneurysms. Prior experience involved relatively small numbers of patients with short follow-up and therefore the risk associated with this subgroup remains incompletely defined. Therefore, we assembled a large HCM cohort with LV apical aneurysms and long-term follow-up in order to clarify clinical course and prognosis. Methods and Results: Of 2,400 HCM patients, 60 (2.5%) were identified by CMR with LV apical aneurysm, 24 to 86 years of age, including 19 (32%) <45 years old; 70% male, and followed for 5.6 ± 3.5 years. Over the follow-up period, 24 patients experienced 31 adverse disease-related complications including: appropriate implantable cardioverter-defibrillator discharge for VT/VF (n=11), received or listed for heart transplant (n=6), heart failure death (n=5), nonfatal thromboembolic events (n=4), resuscitated out-of-hospital cardiac arrest (n=3), and sudden death (n=2). In addition, an intracavitary thrombus was identified in the apical aneurysm in 9 patients without a thromboembolic history. Combined HCM-related death and aborted life threatening event rate was 8.6% per year, nearly 6-fold greater than the 1.5% annual mortality rate reported in the general HCM population. Conclusions: Patients with LV apical aneurysms represent a high-risk subgroup within the diverse HCM spectrum, associated with substantial increased risk for disease-related morbidity and mortality, including advanced heart failure, thromboembolic stroke and sudden death. Identification of this unique HCM phenotype should prompt consideration for primary prevention ICD, and anticoagulation for stroke prophylaxis.

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Abstract 1942: Drug-Eluting Stents for Cerebrovascular Disease: Feasibility, Safety and Intermediate-term Outcomes

Circulation ◽

10.1161/circ.116.suppl_16.ii_418-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Nirav J Mehta ◽

Srihari S Naidu

Keyword(s):

High Risk ◽

Cerebrovascular Disease ◽

Cerebral Circulation ◽

Bare Metal Stents ◽

High Rate ◽

Bleeding Complications ◽

Minor Stroke ◽

Metal Stents ◽

Major Stroke

Background: Cerebral atherosclerosis poses risk of ischemic stroke by embolic or flow-related mechanism. Patients with cerebral vascular disease who are deemed high risk due to critical stenosis or medication failure may have annual risk of recurrent ischemic event in excess of 40%. Major concern with currently used bare metal stents (BMS) is very high rate of restenosis, reportedly > 30%. We analyzed current literature to assess feasibility, safety and short- and intermediate-term outcomes after DES implantation in cerebral circulation. Methods: We performed a systematic literature search for reports that evaluated DES in cerebrovascular disease. Data were extracted to analyze baseline characteristics, vessel selection, technical success, and peri-procedure and intermediate-term outcome. Results: Three studies totaling 88 patients, 94 vessels, and 88 stent placements met the inclusion criteria. Mean age of the patients was 61.5 ± 13.1 years. The success rate for DES delivery was 94% (88/94 vessels). 54 stents were paclitaxel-eluting and 34 were sirolimus-eluting. Peri-procedure complication rate was low with 2 disabling strokes (modified Rankin scale > 2), 1 minor stroke and 2 asymptomatic non-flow limiting dissections. No death or bleeding complications occurred. Stent thrombosis occurred in two cases despite double antiplatelet therapy, accounting for the disabling strokes. At intermediate follow-up (6.5 ± 3.15 months), 4 (5%) cases of restenosis of > 50% vessel diameter were detected, one of which was symptomatic. Major stroke-free survival by Kaplan-Meier analysis was 96% at 9 months. Conclusion: Elective DES delivery in cerebral circulation is technically feasible with low rate of procedural and intermediate-term major stroke or death in high-risk patients. Prospective studies with long term follow-up are required to assess efficacy of DES compared to BMS.

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Breast Cancer in Young Women after Treatment with Irradiation for Hodgkin’s Lymphoma.

Blood ◽

10.1182/blood.v108.11.3333.3333 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3333-3333

Author(s):

Linda Lee ◽

Melania Pintilie ◽

David Hodgson ◽

Michael Crump

Keyword(s):

Breast Cancer ◽

High Risk ◽

Breast Density ◽

Young Women ◽

Cumulative Incidence ◽

Breast Mri ◽

Increased Risk

Abstract BACKGROUND: Women who are survivors of Hodgkin’s Lymphoma (HL) are at increased risk of developing breast cancer (BCa) as a long-term complication due to the use of extended field (mantle) irradiation (RT) of disease above the diaphragm. Many young women are at significantly increased risk of BCa prior to the age at which routine screening mammography is recommended for the general population. The sensitivity of mammography is lower in these women, in part due to increased breast tissue density characteristic of young pre-menopausal women. Currently, there is a paucity of information on the optimal screening modality and surveillance frequency for these women. METHODS: We reviewed the current BCa screening strategies used for this high risk group at our centre and described the incidence, method of detection, and characteristics of secondary BCas in a cohort of 115 women who received supradiaphragmatic RT for HL before age 30 between 1965 and 2000 at Princess Margaret Hospital (PMH) and who subsequently accepted long-term follow-up in a high-risk screening clinic. RESULTS: Median age at treatment was 22 (range 9–30). Radiation fields were mantle in 106 women, modified mantle in 6, and involved field in 3 (median dose delivered: 35 Gy, range 15–60). RT alone was used for 44 patients while 71 received combined modality therapy, of which 45 (65%) received MOPP. Treatment induced amenorrhea occurred in 15 women (median age 38); hormone replacement therapy was subsequently used by 9. Of the 107 women who participated in annual radiographic BCa screening, 95 were screened with mammogram alone, 1 with breast MRI alone, 8 with mammogram and MRI, and 3 with mammogram and ultrasound. Median age at first mammogram was 36; however, median age decreased with more recent year of HL diagnosis (age 40 for women diagnosed before 1985 compared to age 33 for women diagnosed after 1985, p<0.0001). Women with high breast density received MRI screening more often (p=0.02); however, breast density was not significantly associated with previous breast radiation dose or age at last follow-up. Twelve women were diagnosed with BCa in this cohort, following active breast surveillance for a median of 5 years (representing 584 person-years). The 20-year cumulative incidence of breast cancer was 10.9% (95% CI 5.3–18.8%) in this group of women. This was comparable to the 20-year cumulative incidence of breast cancer of 12% (95% CI 8–17%) in all 448 women with HL treated with supradiaphragmatic radiation before age 30 at PMH during the same time period. BCa occurred after a median of 17 years after treatment for HL (range 13–28). Median age at BCa diagnosis was 40 (range 31–51). Seven cancers were detected by physical exam (6 node-positive invasive BCas, 1 in-situ BCa) and 5 were detected on annual mammograms (1 node-positive invasive BCa, 4 in-situ BCas). CONCLUSIONS: Although women in the more recent treatment cohort are receiving their first mammogram at a younger age, the majority of BCas were still detected clinically, and these BCas had less favorable pathological characteristics. More frequent breast imaging should be considered in women who have had supradiaphragmatic RT for HL. Prospective evaluation of breast MRI as a screening strategy for HL survivors has been initiated at PMH in an effort to detect BCa at an earlier stage.

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Mutation Analysis of JAK-1, 2 and 3 in Children with Down Syndrome and Acute Leukemia.

Blood ◽

10.1182/blood.v114.22.5035.5035 ◽

2009 ◽

Vol 114 (22) ◽

pp. 5035-5035

Author(s):

Marjolein Blink ◽

Trudy Buitenkamp ◽

Astrid A Danen-van Oorschot ◽

Valerie de Haas ◽

Dirk Reinhardt ◽

...

Keyword(s):

Down Syndrome ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Lymphoblastic Leukemia ◽

Janus Kinase ◽

Children With Down Syndrome ◽

Activating Mutations ◽

Increased Risk ◽

Frequent Event

Abstract Abstract 5035 Children with Down Syndrome (DS) have an increased risk of developing leukemia, including both acute myeloid (ML-DS), as well as acute lymphoblastic leukemia (DS-ALL). ML-DS can be preceded by a pre-leukemic clone in newborns (transient leukemia-TL), which in most cases resolves spontaneously. Janus Kinase (JAK) 1-3 belongs to a family of intracellular non-receptor protein tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. JAK plays an important role in regulating the processes of cell proliferation, differentiation and apoptosis in response to cytokines and growth factors. Mullighan et al. described JAK 1-3 mutations in non-DS high-risk childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL; PNAS, 2009). In T-ALL, JAK-1 mutations are a frequent event (∼25%) as reported among others by Jeong et al (Clinical Cancer Research, 2008). Mutations in JAK-2 and JAK-3 have been described in TL and ML-DS. Bercovich et al. recently reported mutations within the pseudokinase domain of JAK-2 in DS-ALL patients (Lancet 2008). This activating JAK-2 mutation differs from the V617F exon 14 mutation found in myeloproliferative diseases. However, JAK-1 has never been investigated in Down syndrome leukemias. Therefore we performed mutational analysis of the pseudokinase and kinase domains of JAK-1, 2 and 3 by direct sequencing in 8 TL, 16 ML-DS and 35 DS-ALL samples taken at initial diagnosis. The TL and ML-DS samples were unpaired. In the ML-DS group, 12 patients were classified as FAB M7, 3 as FAB M0 and 1 as FAB M6; all 35 DS-ALL patients were classified as BCP-ALL. Mutations in JAK-1 were found in 1 ML-DS patient (D625R) and in 1 DS-ALL patient (V651M). These mutations were localised in the same region of the pseudokinase domain, but not identical to the activating mutations in JAK1 described in high-risk ALL (Mullighan et al., PNAS 2009). The JAK-1 mutated ML-DS patient had a complex karyogram, and the DS ALL patient a normal karyotype. No events occurred in either of the patients with a follow-up of 2.4 and 3.1 years, respectively. JAK-2 activating mutations at position R683 were found in 5/35 (14.3%) of the DS-ALL patients. These patients had diverse cytogenetic aberrations, and had no events at a median follow up of 4.4 years. In the TL and ML-DS patients no mutations were identified in JAK-2. For JAK-3, 1 TL-patient (13%) and 1 ML-DS patient (6.3%) harboured the A573V-mutation. This activating mutation is previously described in ML-DS patients and the megakaroyblastic cell line CMY ((Kiyoi et al, Leukemia 2007). Because the mutations occur in both TL and ML-DS, this suggests that they do not play a role in the clonal progression model from TL to ML-DS. A mutation at JAK3 R1092C, which to our knowledge has never been reported before, was found in 1 DS-ALL patient. This patient had a deletion on chromosome 12 (p11p13), and was in CCR with a follow up of 5 years. In conclusion, JAK-mutations are rare in DS-leukemias, except for JAK-2 mutations in DS-ALL, which occur in approximately 15% of cases. The rarity of JAK-1 mutations in DS is in accordance with the rarity of T-ALL in DS. Of interest, none of the DS ALL cases with a JAK-2 mutation relapsed so far, which differs from the patients with JAK-2 mutations that were recently in high-risk BCP-ALL. Hence, JAK-2 may be an interesting novel therapeutic target. Disclosures No relevant conflicts of interest to declare.

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Essential Thrombocythaemia in Young Adults: Clinical Characteristics and Outcomes – a Single Center Experience

Blood ◽

10.1182/blood.v120.21.5060.5060 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5060-5060

Author(s):

Grace Kam ◽

Richard Yiu ◽

Ai Leen Ang ◽

Yvonne SM Loh ◽

Yeh Ching Linn ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Disease Progression ◽

Young Patients ◽

Medical Attention ◽

Thrombotic Risk ◽

Risk Of Death ◽

Increased Risk ◽

Thrombosis Rate

Abstract Abstract 5060 Less than 20% of patients with essential thrombocythemia (ET) are diagnosed below the age of 60. Patients with ET have increased risk of thrombosis and bleeding and potential for progression to myelofibrosis (MF) or acute myeloid leukaemia (AML). In limited studies of young patients, the clinical course has been relatively benign with low rates of transformation to AML or MF. Thrombohemorrhagic events are generally few, but higher than that of the general population. This study aims to characterize of a group ET patients diagnosed at age ≤40, their thrombotic and hemorrhagic events, disease progression and treatment given. Patients were identified through a single institution MPN registry. This is an IRB approved registry that captures comprehensive information about patients with ET. Data on patient demographics, treatment, and disease-related events were obtained. Patients were diagnosed from 1975–2011, using either WHO or PVSG criteria depending on date of diagnosis. Kaplan-Meier method was used for survival analysis. 59 patients were diagnosed with ET at age ≤40. Median age of diagnosis was 31. 5years (range 16–40), with a median follow up of 7. 7years (0. 4–33. 8). All were of Asian descent: 81. 4% Chinese, 11. 9% Malay, 3. 4% Indian and 3. 4% Filipino. 40. 7% were male. JAK2 V617F mutation was screened for in 61%. Of these patients, 11 were positive, 25 negative for the mutation. Mean presenting counts were: WBC 10. 7 × 109/L (5. 9–21. 3), Hb 13. 6g/dL (9. 7–16. 4), platelets 957 × 109/L (449–2377). Splenomegaly was noted in 3 patients. 20. 3% had underlying hypertension, 16. 9% hyperlipidemia and 5. 1% diabetes mellitus. One patient had a prior stroke. Another had prior portal vein thrombosis. At diagnosis, 23. 7% were symptomatic, with microvascular symptoms of headache (11. 9%) and giddiness (6. 8%) being most common. The remainder were diagnosed incidentally, on health screening or when seeking medical attention for unrelated conditions. One patient presented with a myocardial infarction at diagnosis, while another had a significant bleeding post hemorrhoidectomy with drop in Hb by >2g/dL (platelet 2457 × 109/L). Based on a history of prior thrombosis, 3 patients were defined as high risk for thrombotic events. 67. 8% of patients had cytoreduction, indications being platelets ≥1500 × 109/L (n=16), presence of risk factors for atherosclerotic disease (n=11) and history/onset of thrombosis (n=5). In 8, the reason for cytoreduction could not be ascertained. Hydroxyurea was most commonly used (62. 7%), followed by anagrelide in 52. 5% and interferon 25. 4%. 5. 1% received busulphan, and 1. 7% 32P. Use of antiplatelet therapy was noted in 83. 8%, most frequently aspirin (76. 5%) and ticlopidine (11. 9%). On follow up, 2 arterial thromboses occurred (stroke, TIA), giving a thrombosis rate of 0. 39%/patients/year. Neither was a recurrent thrombosis. No venous thrombosis or major bleeds occurred. 20. 4% had minor mucocutaneous bleeding; 5 had platelets ≥1500 × 109/L at that time. 3. 4% had disease progression due to MF and another 3. 4% had AML. 3. 4% of patients died due to AML. Median survival was 33. 8years (95% confidence interval 30. 3–35. 5). Initial blood counts, presence of JAK2 and high risk disease status did not correlate with thrombotic risk, risk of death or disease progression. Use of antiplatelet agents and a platelet count ≥1500 × 109/L did not correlate with bleeding risk. Few studies have looked exclusively at young patients with ET. In this group, most patients were asymptomatic and well, ET being diagnosed incidentally. They were predominantly at low risk for thrombosis and other ET-related complications. The period of follow up was comparable to that of other studies and during that time, the rate of complications and risk of disease progression was low. The thrombosis rate of 0. 39% per patient year was less than that reported by other groups (2. 2–2. 6 thromboses/100patients/year) (Leukaemia 2007;21:1218–1223, Clin Appl Thrombosis/Hemostasis 2000;6(1):31–35) but similar to the 0. 74%/patient year reported by Barbui (Blood. Epub. June 13 2012). Overall findings generally complemented those reported by other groups. No risk factors were found to influence the occurrence of complications, but the number of events was small. Follow up of this group of patients over time is essential to see if their disease course remains benign or if complications will increase with time. Soli Deo Gloria Disclosures: Kam: Shire Pharmaceuticals: Consultancy, grant to support the MPN registry Other.

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Risk Of Solid Subsequent Malignant Neoplasms (SMNs) With Extended Follow-Up Of Childhood Hodgkin Lymphoma (HL) Survivors Is Comparable To The Risk In Known High-Risk Groups Within The General Population: Report From The Late Effects Study Group (LESG)

Blood ◽

10.1182/blood.v122.21.2992.2992 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2992-2992

Author(s):

Smita Bhatia ◽

Cor van den Bos ◽

Can-Lan Sun ◽

Jillian Birch ◽

Lisa Diller ◽

...

Keyword(s):

Breast Cancer ◽

Colorectal Cancer ◽

Lung Cancer ◽

High Risk ◽

General Population ◽

Clin Oncol ◽

Cumulative Incidence ◽

Risk Groups ◽

Increased Risk

Abstract Background We describe the pattern and incidence of SMNs with 10 additional years of follow-up of an international cohort (Bhatia, N Engl J Med, 1996; Bhatia, J Clin Oncol, 2003) of children with HL diagnosed between 1955 and 1986 at age 16 y or younger. Methods Medical record review was used to identify SMNs, define vital status and describe therapeutic exposures. Pathology reports served to validate SMNs. Cumulative incidence (CI) utilized competing risk methods. Standardized incidence ratio (SIR) and absolute excess risk (AER/10,000 p-y) utilized age-, gender- and year-matched rates in the general population. Cox regression techniques (using calendar time as time scale) identified predictors of SMN risk. Results The cohort included 1023 patients diagnosed with HL at a median age of 11 y, and followed for a median of 26.8 y (IQR, 16.4-33.7). Eighty-nine percent had received radiation, either alone (22%), or in combination with chemotherapy (67%). Alkylating agent (AA) score was defined as follows: 1 AA for 6 m = AA score of 1; 2 AA for 6 m or 1 AA for 12 m = AA score of 2, etc. The AA score was 1-2 for 54% and 3+ for 16%; 30% did not receive AA. A total of 188 solid SMNs developed in 139 patients (breast [54], thyroid [24], lung [11], colorectal [11], bone [8], other malignancies [80]. Table summarizes SIR (95%CI), CI, and AER by attained age. The cohort was at an 11.1-fold increased risk of developing solid SMNs (excluding non-melanoma skin cancers) compared with the general population (95% CI, 9.4-13.0). CI of solid SMNs was 25.2% at 40 y from HL diagnosis (Fig 1). Among patients aged ≥40 y, 79% of total AER was attributable to breast, thyroid, colorectal and lung SMNs (Table). Thirty-seven patients developed >1 solid SMN; the cumulative incidence of the 2nd SMN was 19.6% at 10 years from diagnosis of the 1st SMN. Breast Cancer: Females (n=41) had a 20.9-fold increased risk, and males (n=3) a 45.8-fold increased risk c/w general population. Age at HL of 10-16 y vs. <10 y (RR=9.7, 95%CI, 2.3-40.6, p=0.002), and exposure to chest radiation (RR=5.9, 95%CI, 1.4-25.9) were associated with increased risk. Among females aged 10-16 y at chest radiation, cumulative incidence was 24.3% by age 45 y, as opposed to 2.6% for those <10 y, p=0.001 (Fig 2). Exposure to AA was associated with a lower risk (RR=0.4, p=0.002). Diagnosis of HL after 1975 was associated with decreased risk (RR=0.25, 95%CI 0.12-0.53), explained, in part by the increasing use of AA after 1975 (78%) vs. before 1975 (61%). By age 40 y, the risk of breast cancer among females exposed to chest radiation at age 10-16 y (18.2%) was comparable to the risk for BRCA1 mutation carriers (15%-20% by age 40 y; Chen, J Clin Oncol, 2007). Lung cancer: Ten of 11 lung cancer cases were diagnosed in males (males: SIR=24.7; females: SIR=3.2, p=0.05); all had received neck/chest radiation. The CI of lung cancer among males was 3.8% by age 50 y, comparable to the risk among male smokers (2% by age 50 y, Bilello, Clinics Chest Med, 2002). Colorectal cancer: There was a 11.5-fold increased risk c/w general population. The CI among those with abdominal/pelvic radiation was 4.1% by age 50 y ; this risk is higher than that observed in individuals with ≥2 first degree relatives affected with colorectal cancer (1.2% by age 50 y, Butterworth, Eur J Cancer, 2006). Thyroid cancer: Survivors had a 22.2-fold increased risk; all developed within radiation field. Females (RR=4.3, 95%CI 1.8-10.4) were at increased risk. Conclusion In this cohort of HL survivors with 20,344 p-y of follow-up, the greatest excess risk of SMNs among those > 40 y was attributable to breast, thyroid, colorectal and lung SMNs. Observed risks for the most common SMNs were comparable to or greater than known high-risk groups within the general population. Disclosures: No relevant conflicts of interest to declare.

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Management Of Pregnancy In Patients With Antithrombin Deficiency

Blood ◽

10.1182/blood.v122.21.216.216 ◽

2013 ◽

Vol 122 (21) ◽

pp. 216-216

Author(s):

Mario von Depka ◽

Stefanie Döpke ◽

Anja Henkel-Klene ◽

Cornelia Wermes ◽

Mahnaz Ekhlasi-Hundrieser ◽

...

Keyword(s):

High Risk ◽

Pregnancy Loss ◽

Conflicts Of Interest ◽

Fetal Loss ◽

Bleeding Complications ◽

Thromboembolic Events ◽

Increased Risk ◽

History Of ◽

At Deficiency ◽

The Mean

Abstract Introduction During pregnancy women have a four- to five-fold increased risk of thromboembolism (TE) compared to women who are not pregnant. Among the most important risk factors for TE in pregnancy is the presence of thrombophilia. Multiple reports have described an association between antithrombin (AT) deficiency and an increased rate of thromboembolic events especially during pregnancy. As the placental development depends on well-balanced pro- and anticoagulant mechanisms, thrombophilia, e.g. AT deficiency may be associated with poor pregnancy outcome. Despite anticoagulation with low molecular weight heparin (LMH) during pregnancy and the postpartum period alone, women with AT deficiency are still at a high risk to develop TE, especially perinatal and during puerperium because of withheld anticoagulation to prevent bleeding complications. Therefore, several guidelines recommend the administration of antithrombin concentrates during high risk situations as pregnancy. Here, we present the results of our study on the usage of AT concentrates in pregnant women with AT deficiency who either suffered from fetal loss or thromboembolism prior inclusion. Methods In total, 22 pregnancies in 19 patients (age: 31.9±4.7; 22-41) with AT deficiency were included in this open-label, single-center study. Ten patients (53%) had a history of fetal loss, 9/19 (47%) patients hat a history of thromboembolism. During all pregnancies AT concentrate (AT-C) was administered, in 18/22 (81.8%) pregnancies LMH was given in addition. Prior pregnancy losses (21/30, 70%) occurred in all trimester (t1: n=11, t2: n=5, and in t3: n=5). Historical live birth rate (LBR) was 30%. Blood samples were collected in all trimesters and postpartum to analyze AT activity and antigen, endogenous thrombin potential (ETP), thrombin-antithrombin-complex (TAT), Fragment 1+2 (F1+2) and c-reactive protein test (CRP). A total of 114 uneventful pregnancies of 113 healthy women served as controls. Furthermore, the mean doses of AT concentrates/kg BW and the mean total number of infusions were calculated. Results In total, 21 pregnancies (95.5%) were successful. Mean total requirement of AT concentrate per pregnancy was 79.454 IU (range: 3.000-272.000 IU) during 27.8 treatment days per pregnancy (range: 1-88). Our data show an increase of F1+2 in the course of pregnancy. Mean levels of F1+2 at t1, t2 and t3 (t1= 255.9 ± 107.6, t2= 360.9 ± 117.4, t3= 545.3 ± 220.3 pmol/L) were significantly higher than in controls (t1= 82.2 ± 43, t2= 140 ± 100.2, t3= 183.5 ± 103.1, p<.001). Mean level of TAT was higher (3.1 ± 1.4 ng/mL) than in controls (1.7 ± 1.6 ng/mL, p=.001) in t1, whereas mean TAT in t2 and t3 was lower than in controls (3.8 ± 1.3 vs. 4.8 ± 1.9, p=.03; 5.0 ± 1.4 vs. 6.1 ± 3.0 ng/mL, n.s., resp.). No thromboembolic events occurred. In patients receiving AT-C, LBR increased from 30% to 95.5% (p<0.001) with a relative risk of 49.0 to develop pregnancy loss without anticoagulant treatment (5.7 – 421.8; 95% CI). Conclusion In patients with AT deficiency receiving AT concentrate and LMH we could demonstrate a significant increase of LBR from 30% to 95.5%. Furthermore, no thromboembolic events occurred, though almost half of the patients had a history of thromboembolism. There was no clear evidence of increased hypercoagulability. We conclude that combined AT concentrate and LMH are safe and efficacious for mother and child in preventing thromboembolism and pregnancy loss. Further studies to evaluate the exact mode of anticoagulation and benefit of combining AT concentrate and LMH are warranted. Disclosures: No relevant conflicts of interest to declare.

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Mutational Studies Using Next Generation Sequencing in High Risk Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia Patients Treated with Azacitidine (High risk MDS 2009 protocol from CETLAM Group)

Blood ◽

10.1182/blood.v126.23.2905.2905 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2905-2905

Author(s):

Marta Cabezon ◽

Joan Bargay ◽

Blanca Xicoy ◽

Laura Palomo ◽

Sílvia Marcé ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Treatment Response ◽

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Myeloid Leukemia ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Increased Risk ◽

Acute Myeloid

Abstract INTRODUCTION: Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms originated in hematopoietic stem cells, characterized by citopenias, dysplasia in one or more cell lines, ineffective hematopoiesis and an increased risk of progression to acute myeloid leukemia (AML). Treatment of MDS depends on subtype and prognostic category. DNA methyltranferase inhibitors are approved for high risk MDS. Over the past decade, the application of new high-throughput technologies to the study of MDS has led to the identification of several recurrently mutated genes. These include genes producing proteins involved in RNA splicing, DNA methylation, chromatin modification, transcription, DNA repair control, cohesin function, RAS pathway, and DNA replication. There is a significant overlap between the genes mutated commonly in MDS with those found in AML. Mutation status is not widely used to select treatment in MDS. The aim of this study is to define the mutational status of MDS and secondary AML (sAML) patients at diagnosis that have been treated with azacitidine (AZA) to see if it could help to discriminate which patients will respond from those who will not. MATERIAL AND METHODS: A prospective study was performed on 36 patients with MDS and sAML treated with AZA. Genomic DNA was obtained from bone marrow at diagnosis. SeqCap EZ and KAPA Library Preparation Kit (Roche) reagents have been used to enrich DNA of 83 genes implicated in myeloid neoplasm. The customized panel has been analyzed in MiSeq Illumina platform with 150bp paired-end reads. Samples were preliminary analyzed using Illumina MiSeq Reporter and Variant Studio softwares. Data from response to treatment and survival have been collected from all patients. RESULTS:The mean depth of the targeted resequencing per base was 685-fold. After filtering all the variations obtained for quality, biological consequence and discard the known SNPs, we have obtained 162 variations, including 145 single nucleotide variants (SNV) and 17 insertions/deletions. All patients harbored at least 1 alteration with a mean of 4.5 variants per sample. The average of alterations detected in each cytological category can be observed in Table 1.Table 1.Average abnormalities detected by cytological category.Nº patientsAverage of alterations detected for patient (range)sAML104,8 (1-8)RAEB-274,9 (2-8)RAEB-1123,7 (1-6)RCDM54,4 (3-7)RCDM-RS16RARs11The most frequent altered genes have been TP53, TET2 and DNMT3A. The numbers of variations detected for each gene are represented in Table 2.Complete results, including correlation with treatment response will be presented in the meeting.Table 2.Number of variations in each gene.GeneNº of variations foundNº of diferent variationsNº of patients with variationsFrequency of variationsTP5322191952,8%TET214101027,8%DNMT3A88822,2%CREBBP75719,4%SRSF271719,4%ASXL165616,7%U2AF162616,7%EP30053513,9%STAG255513,9%CUX144411,1%ETV643411,1%MLL (KMT2A)43411,1%RUNX14438,3%BCOR3338,3%CDH133338,3%CTNNA13238,3%EZH23338,3%GCAT3338,3%MLL2 (KMT2D)3338,3%NF13338,3%PDGFRB3338,3%SH2B33338,3%TGM23238,3%UMODL13338,3%CEBPA2125,6%CSF3R2225,6%GATA22125,6%PHLPP12225,6%RAD212225,6%SF3B12125,6%SUZ122225,6%TIMM502125,6%Others*1112,8%*ABL1, BCORL1, CALR, CDH3, IDH2, KRAS, LUC7L2, NPM1, NRAS, PHF6, SF3A1, SFPQ, SMC3, TERT, WT1, ZRSR2. CONCLUSIONS: Targeted deep-sequencing technique is a good tool to study mutational profile in MDS and sAML. SNV are the most frequent type of alteration found in our cohort. The patients with sAML and RAEB-2 present more variations than patients with RAEB-1. The rest of groups are less representing to be evaluated. The most affected genes match with those described in the literature, with some exceptions that need to be studied in more detail. We expect to predict in advance which patients are going to respond when we study the correlation of mutational analysis with treatment response. Acknowledgments: Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Spain (PI 11/02519); 2014 SGR225 (GRE) Generalitat de Catalunya; Fundació Josep Carreras, Obra Social "La Caixa" and Celgene Spain. Diana Domínguez for her technical assistance Disclosures Valcarcel: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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