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From17.04.2013 Induction therapy as per MLL-BABY-2006 protocol, intermediate risk group

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Area 0.35m2, age 5 months

Doses of Dexamethasone and cytostatic agents – 2/3 of dose, as per area till 29.04.2013, from 30.04.2013 – ¾ of the dose.

Endolumbar №7 - Methotrexate 6 mg, Cytosar 20 mg, dexamethasone 1 mg (17.04.2013, 24.04.2013, 30.04.2013, 08.05.2013, 15.05.2013, 22.05.2013, 29.05.2013)

1 day 17.04.2013 – dose of dexamethasone 0.2 mg intravenous push, Lp

4th day of induction 20.04.2013 – full dose of Dexamethasone 1.5 mg/day, from 08.05.2013 Dexamethasone dose 1.75 mg/day, from 24 May 2013 stop Dexamethasone.

8th day of induction 24.04.2013 – Vincristine 0.35 mg, Rubomicine 10.5 mg Lp

15th day of induction 01.05.2013 – Vincristine 0.39 mg, Lp (30.04.2013), КМП (30.04.2013)

22nd day of induction 08.05.2013 – Vincristine 0.39 mg, Rubomicine 11.8 mg, Lp

29th day of induction 15.05.2013 – Vincristine 0.39 mg, Lp

36th day of induction 22.05.2013 - Vincristine 0.39 mg, Lp, КМП

Vesanoid 1 capsule/day 22.05.2013 – 28.05.2013, total 7 capsules.

43rd day of induction 29.05.2013 – Lp, КМП

Therapy results:

8th day of induction 24.04.2013 FBC: Erythrocytes-3.5x10^12/l, HB-96g/l, Thrombocytes – 173x10^9/l, Leucocytes – 2.7 x 10^9/l, Blasts 14%, с/я 12%, lymphocytes – 68%, monocytes 6%

Liver +2cm, Spleen +2.5cm.

30.04.2013 14th day of induction

Examination of bone marrow punctate with myelogram count 30.04.2013 – The drug was few-celled and polymorphic. Slight increase in the quantity of blasts up to 7.2%.

Bone marrow test using flow cytometry dated 30.04.2013 – tumour blasts 6.054%.

Real time PCR bone marrow test dated 30.04.2013 - expression of chimeric gene MLL-AF9 (t(9;11)), observed, the value of normalized number of copies is 8.708%.

Liver size +3.5cm, Spleen size +1.5cm

36th day of induction 22.05.2013

In FBC dated 22.05.2013 – leucocytes 1.44x10^9/l, erythrocytes 3.3 x10^12/l, haemoglobin 98 g/l, thrombocytes 191 x10^9/l, lymphocytes 73%, monocytes 19%, ESR 25 mm/h.

Examination of bone marrow punctate with myelogram count dated 22.05.2013 – cellular, Acute varicose of erythroid lineage, significantly expressed signs of diserythropoesis, acute shrinkage of granulocytic lineage, mature neutrophils – solitary.

Bone marrow test using flow cytometry method dated 22.05.2013 – tumour blasts 0,000%, B-linear regeneration 0.116%.

Real time PCR bone marrow test dated 22.05.2013 - found expression of chimeric gene MLL-AF9 (t(9;11)), the value of normalized number of copies is 0.02%.

Bone marrow test using FICH method for 11q23 dated 22.05.2013 – 1000 nucleuses analysed, reforming of MLL gene not observed.

43rd day of induction 29.05.2013

In FBC dated 30.05.2013 – leucocytes 2.0x10^9/l; erythrocytes 4.3x10^12/l; haemoglobin 119 g/l; thrombocytes 227x10^9/l; neutrines 39%, lymphocytes 37%, monocytes 24%, ESR 15 mm/h.

Bone marrow punctate test with myelogram count dated 29.05.2013 – low cellular drug, polymorphic, blasts 0.4%, in the granulocyte germ cells hypogranulization of mature cells is found, also observed are shadows of destroyed cells. Signs of diserythropoesis. 2% unclear cells found carrying basophil cytoplasma, with condensed mound like nuclear structure. Nucleus is large, round, nucleoids 0-1-0. Megakaryocytes and thrombocytes in sufficient numbers.

Bone marrow test using flow cytometry method dated 29.05.2013 – tumorous blasts 0.000%, B-linear regeneration 0.726%.

Real time PCR bone marrow test dated 29.05.2013 – Chimeric gene MLL-AF9(t(9;11)) expression found, the value of normalized number of copies is 0.024%.

Spleen palpating +1-1.5 cm.

Specifics of therapy:

1) Since admittance the patient is being administered meronem and metronidazole i/v, does not have fever.

Due to serious condition (hyperleucocytosis, lymphoproliterative syndrome, kidney deficiency) the patient was shifted to the intensive care unit.

On 17.04.2013 Broviak catheter for ALV was readily implanted. From 17.04.2013 (before the implant of the catheter) the patient had pyretic fever.

Going through the acute tumour decomposition syndrome, being administered dopamine micro-fluid. From 18.04.2013 Vankomycine i/v was added, from 19.04.2013 Fluconazole i/v was added. High fever persists, with ample mucous discharge from nose. From 19.04.2013 Tamiflu was added. On 19.04.2013 and 20.04.2013 the patient received only 4 doses of Leucovorin 10 mg i/v per dose. After prescription of Tamiflu and Leucovorin temperature lowered to sub-febrile levels. From 24.04.2013 there is stable normalization of temperature.

Against the backdrop of massive antibacterial therapy the clinical picture of entheropathy, stool culture – growth of Gram-negative micro flora was not found, there is ample growth of Enterococcus faecalis, staphylococcus haemolyticus. Fungal growth not found. Oral Vankomycine was added to therapy, entheropathy gradually stopped. The patient’s diet includes: Lactose free Enfamil + mother’s milk.

On 24.04.2013 the patient was detached from ALV and on 26.04.2013 he was transferred to Paediatric Oncology Ward №1.

From 31.05.2013 due to reinstatement of blood creation the antibacterial and antifungal therapies were discontinued.

 

2) Replacement therapy with irradiated blood components.

3) Erosive dermatitis in gluteal area.

4) During cerebrospinal fluid test dated 22.05.2013 significant xanthosis of cerebrospinal fluid is noticeable. At the same time the cerebrospinal fluid contains leucocytes 9.3x10^6/l; erythrocytes 1280x10^6/l (mostly unchanged), increase in protein with each test of cerebrospinal fluid during schedules cerebrospinal paracentesis – from 0.5g/l to 8.3g/l. During cerebrospinal fluid test using cytospin method – against the backdrop of predominantly unchanged erythrocytes a small quantity of macrophage, monocytes and lymphocytes. On 24.05.2013 cerebrospinal puncture was carried out for diagnostic purposes to eliminate the flow of sub-acute virus-associated meningoencephalitis. Alongside the spleen started palpating to +1.5cm.

During cerebrospinal fluid test of 24.05.2013 – colourless, transparent, leucocytes 1.3x10^6/l, erythrocytes 5x10^6/l.

During cerebrospinal fluid test using cytospin method – cellular drug, transported over the monocytes, singular macrophages and lymphocytes.

Biochemical test of cerebrospinal fluid dated 24.05.2013 – protein 1.5g/l, glucose 5.3 mmol/l, bilirubin 1 mmol/l, chloride 111.3 mmol/l.

Bacterial culture of cerebrospinal fluid dated 24.05.2013 – Negative.

PCR test of cerebrospinal fluid dated 24.05.2013 – herpes virus of types 1 and 2, EBV, CMV, herpes virus type 6, Aspergillus fumigatus DNA, Candida albicans. Toxoplasma gondii, Chlamydia trachomatis not found.

PCR blood test dated 24.05.2013 – Hepatitis B, C virus, herpes virus types 1 and 2, EBV, CMV, herpes type 6 virus not found (negative).

PCR urine test dated 24.05.2013 – herpes virus types 1, 2, 6, CMV, polyomavirus not found.

Serologic blood test dated 24.05.2013 – antibodies to EBV –caps IgM<0?1, incipient IgM 0.08, caps IgG 150, incipient IgG 7, nuclear IgG99;

CMV antibodies – IgM 0.1, IgG 108, avidity IgG 75%

Chlamydia pneumonia antibodies IgM 0.1, IgG 92.9

24.05.2013 MRI of brain – combined hydrocephaly. Subcortical leukoencephalopathy.

24.05.2013 Patient checked by neurologist – Post chemotherapy polyradiculoneuropathy. Miatonic syndrome. Hyperactivity syndrome. Intracranial hypertension syndrome.

27.05.2013 Electroencephalogram – Moderate overall changes in BEA of brain. Signs of activation of synchronizing structures of brain, reduction in cerebral cortex responsiveness in RPS. Periodic indistinct regional slowdowns in left parietal-occipital region. Solitary sharp theta-potentials in parietal-occipital regions. Actual epileptiform activity not noted.

5) Against the backdrop of taking Vesanoid the clinical picture of intracranial hypertension, acute hypoproteinemia and hypoalbuminaemia, moderate peripheral edema – the patient is given diacarb, Analgin, Ondancetron i/v, twice was administered Dexamethasone i/v dose of 0.3ml, intravenous micro-push albumin 10%.

Consolidation of I ImRG, Low MTX + L-ASP+ATRA, dose calculation – ¾, area 0.38m2

1st week 11.06.2013 – Methotrexate i/v push 100% dose 11.06.2013, 6-mercaptopurin oral daily 100% of dose, L-asparaginase 2850 UNITS i/m 12.06.2013.

2nd week 18.06.2013 –

Agranulocytosis, methotrexate intravenous 50% of dose, L-asparaginase 2850 UNITS i/m 19.06.2013.

By 25.06.2013 agranulocytosis worsened, the fever increased, 6-mercaptopurin was discontinued, administered a course of meronem and metronidazole intravenous, transfusion of Octagama 2.5 g. on 25.06.2013 and 26.06.2013 transfusion of erythrovzvesi was conducted selectively.

3rd week 04.07.2013 –

Started administering 6-mercaptopurine again in 50% of dose, L-asparaginase 2850 UNITS i/m.

On 05.07.2013 cerebrospinal puncture (methotrexate 6 mg, Cytosar 20 mg, dexamethasone 1 mg) on 04.07.2013 administration of methotrexate skipped.

4th week 11.07.2013 –

Methotrexate intravenous push equivalent to 50% of the dose 11.07.2013, 6-mercaptopurine oral daily equivalent to 50% of dose, L-asparaginase 2850 UNITS i/m 12.07.2013.

5th week 18.07.2013 –

Methotrexate intravenous push equivalent to 100% of dose 18.07.2013, 6-mercaptopurine oral daily equivalent to 100% of dose, methotrexate i/m equivalent to 100% of dose 18.07.2013, intravenous drop Rubomicine 8.5 mg 18.07.2013. L-asparaginase 2850 UNITS i/m 19.07.2013, cerebrospinal puncture (methotrexate 6 mg, Cytosar 20 mg, dexamethasone 1 mg) 18.07.2013 (during cerebrospinal fluid test using immunophenotyping – atypical tumorous cells with phenotype CD45dim+CD10+CD19+ were not found, during cytospin test – the drug was moderately cellular, transported to monocytes, lymphocytes and macrophages).

22.07.2013 checked by the neurologist – Diagnosis: PACNS hypoxic genesis of light form, late rehabilitation period. Pyramidal deficiency in lower limbs syndrome. Impressions about epi-process not developed, no signs requiring EEG –video monitoring.

6th week 25.07.2013 –

Agranulocytosis, the patient was given L-asparaginase i/m 2850 UNITS on 25.07.2013, 6-mercaptopurine and methotrexate discontinued. The spleen stopped palpating. On 26.07.2013 selective transfusion erythrovzvesi was conducted.

Considering the prevailing agranulocytosis and no possibility of conducting re-induction chemotherapy, the baby was given a course of Vesanoid from 30.07.2013 to 12.08.2013 as per 1 capsule/day against the backdrop of the accompanying therapy.

Since 05.08.2013 the spleen again started palpating to +1cm. on 12.08.2013 the patient came out of agranulocytosis.


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