Dear colleagues,

I would like to kindly ask your opinion and recommendation on further management of a BKV driven TA-TMA early post alloHSCT - now on eculizumab and cidofovir treatment; persistent BK viremia and renal failure, TMA seems to be controlled on eculizumab.

Main questions would touch the antiviral therapy:

1. how to administer cidofovir during renal failure? who would continue?

2. is combination with leflunomid rational?

3. shall we proceed to organize BKV-specific T cells (not available in our center, but possibly feasible in cooperation if other measures shall not be successful)?

Question on eculizumab:

5. may we proceed to maintance regimen? (terminal complement complex formation well suppressed after 2 doses, however the cascade above is still active...) referring to Jodele et al. / Blood Reviews 29 (2015) 191–204

Details below:

12yo boy with AML-M5 t(10,11) underwent MUD (10/10) HSCT in 1stCR on June 1, 2016, myeloablative conditioning (BuCyMel), ATG, CsA+MTX as GvHD profylaxis, unmanipulated PBSC as source

Post transplant course, BKV and TA-TMA onset:

- day +11 - severe hemorrhagic cystitis gr. III (clots, no clear obstruction seen)

- BK virus proven in urin (billions /ml), not in blood

- day +14 - 1st dose of cidofovir (5mg/kg i.v. w/ probenecid)

- day +15 (16.6.2016) engraftment of Le/Ne

- day +18 (19.6.2016) - sudden refractoriness to thrombocyte transfusions (2 apheresis units of Tr per day with no increase)

- day +21 (22.6.3016) arterial hypertension progressed with requirement of 2 antihypertensive drug combination

- day +21 prolonged epistaxis, for several days

- day +21 - 2nd dose of cidofovir (1mg/kg i,v. w/o probenecid)

- day +23 and on - acute renal failure with creatinin rising and GFR decrease, fluid retention and severe metabolic acidosis

- day +23 skin rash and diarrhea evaluated as acute GvHD - corticosteroids added to treatment

- day +26 (27.6.2016) - quantitative and qualitative mental and consciussness disturbances, rapid progression of renal failure; GI bleeding; uncompensated metabolic acidosis;

- withdrawal of cyclosporin A and other neurotoxic drugs

- day +27 BKV in plasma (25400 copies /ml)

- day +27 (28.6.2016) - administration of 1st eculizumab, complement testing confirming high activation (sC5b-9, ...)

- rapid clinical improvement - was spared dialysis, consciousness improved, GI bleeding stopped, hypertension normalized;

- hemorrhagic cystitis only termporarily improved, stays gr. III-IV later

- laboratory: eculizumab effective, full blockade observed - daily CH50 very low (2 to 4 CH50/ml (ref range 48-103 CH50/ml), sC5b-9 levels pending, LDH normalized

- 2 cidofovir low-doses (0.5mg/kg/ every other day) given

- day + 34 - eculizumab 2nd dose (5.7.2016) administered

- during the last 6 days the renal parameters increased again, the hemorrhagic cystitis persists unimproved

Renal failure:

- fluids balanced on low dose diuretics

- metabolic acidosis corrected on continuous Na bicarb

creatinin currently 206 umol/L = 2.3 mg/dL (see graph attached)

urea currently 23 mmol/L (see graph attached)

daily CH50 values are all below the quantifiable range of the assay used (very low) after eculizumab.

We will be most grateful for any good idea. Thank you.

With kind regards,

Peter Svec

Peter Svec, MD, PhD

Department of Pediatric Hematology and Oncology

Comenius University Children's Hospital

Limbova 1, 833 40 Bratislava, Slovakia