A Case of Biphenotypic Acute Leukemia
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  • 1. INTERESTING CASE OF DEEP VEIN THROMBOSIS PROF.DR.K.H.NOORUL AMMEN’S UNIT M5 DR.M.ARIVUMANI
  • 2.
    • 20 Year old Miss.Priya admitted on 18/7/11 with
    • c/o fever 1 month duration
    • intermittent fever initially,then she had continuous fever,low grade,not asssociated with chills or rigors
    • h/o swelling over left leg 10 days duration
    • associated with pain
    • constant pain limiting movements
    • h/o easy fatiguability +
  • 3.  
  • 4.
    • H/o body pain +
    • No h/o joint pain
    • No h/o breathlessness
    • No h/o palpitation
    • No h/o chest pain,syncope
    • No h/o abdominal distension,pain
    • No h/o easy bruisability,rashes
    • No h/o bleeding tendencies on admission
    • No h/o trauma
  • 5.
    • Past history
    • no h/o similar illness in the past
    • h/o bleeding gums occasionally +
    • Personal history
    • regular menstrual cycles.
    • Family history
    • nil significant
  • 6. Examination
    • General examination
    • Patient concious/oriented
    • febrile
    • pallor +
    • no cyanosis,no clubbing,no icterus
    • swelling of left lower limb +
    • no generalised lymphadenopathy
  • 7.
    • Vital signs
    • PR-108/min,regular,felt in all peripheral vessels
    • BP- 110/70mmhg
    • RR-20/min
    • Temp- 101 degree F
  • 8.
    • Systemic examination
    • CVS- S1S2 Heard
    • systolic murmur +
    • RS-NVBS heard.no added sounds
    • P/A-soft
    • CNS-NFND
    • L/E of left leg-swelling of left leg +,tender
    • homans sign +
  • 9.
    • With the above clinical profile pt got admitted in vascular surgery dept.
    • Provisional diagnosis of DVT(wells score 3) was made
    • Hand held doppler revealed no significant thrombus in deep veins
    • Patient was started on INJ.Heparin 5000u qid.
    • Symptoms started improving after two days
  • 10.
    • On third day patient developed menorrhagia and malena,so heparin stopped.
    • Patient had persistent fever and sever pallor so physician opinion sought.
    • We took over the case
  • 11. While receiving in medical ward
    • Patient had h/o fever
    • h/o breathlessness
    • h/o bleeding pv
    • h/o malena
    • h/o swelling over left leg(swelling decreased,pain subsided)
  • 12. Examination
    • Patient concious,irritable
    • Severe pallor +
    • Dyspnoeic,tachypnoeic
    • Sternal tenderness +
    • No cyanosis,no clubbbing,no icterus
    • No lymphadenopathy
  • 13.
    • Vitals
    • PR-120/min
    • RR-38/min
    • BP-100/70 mmhg
    • febrile
    • Systemic examination
    • CVS-S1S2+,systolic murmur +
  • 14.
    • RS-NVBS+,occasional creps +
    • P/A-Liver 4cm palpable below RCM Spleen 3cm palpable below LCM
    • CNS-NFND
  • 15. INVESTIGATIONS
    • CBC-Hb-5.4 grams
    • TC 10400
    • DC P40 L 60
    • ESR 25/52
    • PCV 16%
    • Platelet-58000
    • RFT- WNL
    • LFT-WNL
    • Urine routine-WNL
  • 16.
    • QBC-negative
    • WIDAL-negative
    • MSAT-negative
    • Urine c&s- no growth
    • Blood c&s-no growth
    • Peripheral smear-
    • RBC count reduced,normocytic RBC’S with hypochromic cells
    • WBC-monocytosis observed,few atypical monocytoid cells seen
    • Severe thromobocytopenia observed
  • 17.
    • Reticulocyte count-2.3%
    22/7 24/7 PT 15.4 sec 17.8sec PTT 34.0sec 25.6sec INR 1.5 1.2
  • 18.
    • HIV –negative
    • D-Dimer 5.35 mcg( >0.5mcg positive)
    • FDP- 20mcg/ml( >5mcg/ml positive)
    • LDH-528U/L(135-214u/l)
    • Serum homocysteine- WNL
    • APLA-WNL
    • Protein c,PROTEIN s-not affordable
  • 19.
    • USG abdomen
    • hepatosplenomegaly +
    • no para aortic nodes
    • no free fluid
    • Chest xray normal
    • ECG- Sinus tachycardia
  • 20. HEMATOLOGIST OPINION OBTAINED AT RGGGH
    • CBC- TC 2800
    • DC P20%, L 10% ,
    • ATYPICAL CELLS 70 %
    • HB 7.3 gms/dl
    • PCV 21%
    • Platelet 54000
    • ESR 18/42
  • 21.
    • Peripheral smear
    • numerous atypical cells +
    • platelets decreased
    • Hematologist advised
    • BMA
    • To start T.Allopurinol 1 tds
    • While waiting for BM diagnosis patient was managed with packed cells, FFP,Platelet concentrate,antibiotics
  • 22. BMA done on 29/7/11
  • 23.  
  • 24.  
  • 25. Lymphoblast & myeloblast
  • 26. lymphoblast
  • 27. Myeloblast
  • 28. myeloblast
  • 29. BMA REPORT
    • Marrow contains 90% blast cells comprising of both lymphoblast and myeloblast
    • Final diagnosis
    • BILINEAL OR BIPHENOTYPIC ACUTE LEUKEMIA with Deep vein thrombosis
  • 30. BIPHENOTYPIC ACUTE LEUKEMIA(BAL)
    • Biphenotypic acute leukaemia is an uncommon type of leukemia.
    • The precise incidence is uncertain, it is likely to account for approximately 5% of all acute leukemias.
    • BAL can be de novo or secondary to previous cytotoxic therapy.
    • It has been included in the WHO classification of haemopoietic malignancies as acute leukaemia of ambiguous lineage
  • 31. WHO classification of hematological malignancies
    • Chronic myeloproliferative disorders
    • Myeloblastic syndrome
    • Leukemia of myeloid origin
    • Leukemia of lymphoid origin
    • Leukemia of ambiguous origin
  • 32.
    • Acute leukemias of ambiguous lineage include
    • 1.Undifferentiated acute leukemia
    • Leukemic cells that can not be classified as
    • either myeloid or lymphoid cells
    • 2. Acute leukemias of mixed phenotype.
    • Mixed lineage or biphenotypic acute leukemia
    • where both types of cells are present.
  • 33.  
  • 34. EGIL scoring for biphenotypic acute leukaemia. The score for each lineage is calculated and if that lineage score > 2, that lineage is present. EGIL-European group for immunological classification of leukemia POINTS T CELL LINEAGE B CELL LINEAGE MYELOID LINEAGE 2 POINTS CD 79 CD3 TCR MPO 1 POINTS cCd22 CD10 CD19 CD20 CD2 CD5 CD8 CD10 CD13 CD33 CDw65 CD117 0.5 POINTS Tdt CD24 Tdt Cd17 cd1A CD15 CD15 CD24
  • 35. TREATMENT
    • BAL has proven to be very difficult to treat with many cases being resistant to induction chemotherapy and those that enter remission have a high risk of relapse.
    • There is no agreement on how the disease should be treated.
    • The majority of patients receive treatment according to the morphology of the blasts, with either AML or ALL induction.
    • If patients enter complete remission, consideration should be given to consolidation with stem cell transplantation.
  • 36. Copyright ©2009 Ferrata Storti Foundation Zheng, C. et al. Haematologica 2009;94:1778-1780 Figure 1. Treatment schedule on the BAL patients
  • 37. When immunophenotyping is not possible steroid trial should be started
  • 38.
    • Prognostic factor for CR
    • age<60 years
    • Prognostic factor for survival
    • age<60years
    • achievement of CR
    • The prognosis of biphenotypic acute leukemia patients is poor when compared with de novo acute myeloid leukemia or acute lymphoblastic leukemia.
    • Biphenotypic acute leukemia patients have abnormal karyotype, extramedullary infiltration, relapse, and resistance to therapy after relapse
  • 39. DVT IN ACUTE LEUKEMIA
    • Studies have demonstrated that the risk of VTE associated with the hematological malignancies acute leukemia, lymphoma, and multiple myeloma is considerable.
    • Contributing factors include hypercoagulablefactors,Hyperleukocytosis,
    • antineoplastic therapies such as high dose corticosteroids, L-asparaginase, and new immunomodulatory agents; central venous catheters; and hematopoietic growth factors .
  • 40.
    • Primary and secondary pharmacological prophylaxis can be problematic in these patients who are often thrombocytopenic. Strategies to prevent VTE, especially upper extremity catheter-associated thrombosis need to be developed.
  • 41.
    • The incidence of VTE at diagnosis was
    • 1.2 % in ALL,
    • 3.2% in APL and
    • 2.5 % in non-M3 AML.
  • 42.
    • Thromboembolism is a well recognized complication of hematologic malignancy. The pathogenesis of the cancer-related prothrombotic state are
    • 1. activation of blood coagulation via procoagulant substances,
    • 2.impairment of fibrinolytic pathways,
    • 3.alterations of endothelium toward a thrombogenic state
    • Journal of Thrombosis and Haemostasis, 3: 1985–1992
  • 43.
    • The classic &quot;gold standard&quot; is contrast venography. Although very accurate, this method requires radiologic facilities and expertise and is invasive and sometimes uncomfortable for the patient.
    • Ultrasonography, with noncompressibility of the vein as the sole criterion, has largely replaced contrast venography
    • investigation is limited to the femoral vein in the groin and the popliteal vein in the popliteal fossa
  • 44.
    • The combination of the assessment of clinical probability and the measurement of the D-dimer has been shown to be useful. The clinical probability can be best assessed by wells score, which results in a classification of either DVT likely or DVT unlikely.
    • D-Dimer is a degradation product of cross-linked fibrin and therefore concentrations of D-dimer below a certain cut-off level are considered to indicate the absence of thrombosis(higher negative predictive value)
  • 45. Wells Probability score for DVT <2 DVT unlikely, >2 DVT likely Clinical features points Active cancer 1 Paralysis,paresis,recent immobilisation of lower extremities 1 Localised tenderness along deep venous system 1 Entire leg swollen 1 Calf swelling>3cm larger than asymptomatic side 1 u/l pitting edema 1 Collateral superficial veins(non varicose) 1 Previously documented DVT 1 Alternative diagnosis as likely or more likely than DVT -2
  • 46. NCCN Guidelines for Deep Vein Thrombosis Treatment in Cancer Patients
    • The therapy guidelines are aimed at in-hospital treatment and list the following drugs for anticoagulation:
    • *Unfractionated heparin: 5,000 units S.C TDS
    • *LMWH-dalteparin, enoxaparin, or tinzaparin
    • *Pentasaccharide, fondaparinux, 2.5 mg subcutaneous daily
    • *If patients cannot take anticoagulation medications, compression devices can be used, including graduated compression stockings
  • 47.
    • The guidelines suggest using low-molecular-weight heparin for long-term therapy for prevention of recurrent deep vein thrombosis in patients with advanced or spreading cancer. The minimum time for treating deep vein thrombosis is 3–6 months; pulmonary embolism requires 6–12 months of treatment.
  • 48.
    • Migrating venous thrombosis in acute leukemia
    • Musil D , Krc I .
    • Source: Department of Vascular Diseases, Institute of Pathological Physiology, Palacky University, Czech Republic.
    • Abstract: We present a 55-year-old man with acute migrating thrombophlebitis and deep vein thrombosis of muscle veins in both calves indicating occurrence of acute myelomonocytic leukemia. Thrombosis of superficial and deep veins of the lower limbs arose in spite of the adequate anticoagulation therapy with warfarin
  • 49. Venous thromboembolism in patients with acute leukemia, lymphoma, and multiple myeloma
    • Ted Wun a , b , c, d, , and Richard H. White e
    • a Division of Hematology and Oncology, UC Davis School of Medicine, USA
    • Abstract
    • The association of malignancies and venous thromboembolism (VTE) is a long held axiom in medicine. A growing number of studies have demonstrated that the risk of VTE associated with the hematological malignancies acute leukemia, lymphoma, and multiple myeloma is considerable. In fact, the incidence associated with these malignancies exceeds that for many solid tumors.
  • 50. Review Article Thrombosis in children with acute lymphoblastic leukemia: Part III. Pathogenesis of thrombosis in children with acute lymphoblastic leukemia: effects of host environment
    • TE in association with childhood ALL is a multifactorial entity resulting from the interaction of the disease, chemotherapy and its effects, and possible prothrombotic states inherent to the host. The few studies conducted so far in children with ALL have reported wide variability in the prevalence of prothrombotic defects and its impact on the risk of TE.
    • Thrombosis Research Volume 111, Issue 6 , 2003, Pages 321-327
  • 51. Venous thromboembolism in patients with acute leukemia: incidence, risk factors, and effect on survival
    • Journal of american society of hematology ( APRIL 23 2009)
    • Thombosis was a clinical presenting manifestation in 13 patients of 379 (3.4%, 95% CI 1.8%–5.8%): one with ALL (1.4%), three with APL (9.6%), and nine with non-M3 AML (3.2%). After exclusion of the four patients with arterial ischemic stroke (two with APL and two with non-M3 AML),the incidence of VTE at diagnosis was 3.2% in APL and 2.5%in non-M3 AML
  • 52.
    • References:
    • Harrisons principles of internal medicine 17th ed
    • Williams textbook of hematology 8 th ed
    • Wintrobe’s clinical hematology 12 th ed
  • 53.