Download Effectivity and Toxicity

“Fall in Leukocyte Count for Monitoring of
(1) Anti-Cancer,
(2) Anti-Infective and
(3) Immunosuppressive
Drug Therapy“
Disclosures:
NO
Frieder Keller
Nephrology
F Stegmeier
Targeted Cancer Therapies in the Twenty-First Century: Lessons From Imatinib
Clin Pharmacol Ther. 2010; 87: 543-552.
Effektivitaet
Effectivityund
andToxizitaet
Toxicity
 CE 
1   50 
 C 
H
75
Effekt (E)
E
100
Emax
Effectivity
Toxicity
50
25
0
0
10
20
30
Konzentration (C)
40
50
Effektivitaet
Effectivityund
andToxizitaet
Toxicity
 CE  CE50 
1   50

C


100
H H
75
Effekt (E)
EE
Emax
Effectivity
Toxicity
50
25
0
0
10
20
30
Konzentration (C)
40
50
Gurney H
How to calculate the dose of chemotherapy
British Journal of Cancer (2002) 86, 1297 – 1302
CAF = cyclophosphamide, adriamycin/ doxorubicin, 5FU
Carus A.
Impact of baseline and nadir neutrophil index in non-small cell lung cancer and ovarian cancer patients:
Assessment of carbopoplatin chemotherapy for resolution of unfavourable neutrophilia
J Translational Med. 2013, 11: 189
Survial benefit
<= neutropenia < 1.0 x 10^9 /L
<= neutrophils > 3.0 x 10^9 /L
Kohei Shitara
Meta-analysis of leukopenia as a prognostic factor in patients with malignant disease
undergoing chemotherapy
Cancer Chemother Pharmacol. 2011; 68: 301–307
Mayer RJ; RECOURSE Study Group.
Randomized trial of TAS-102 Trifluridine / Tipiracil for refractory metastatic colorectal cancer.
N Engl J Med. 2015; 372: 1909-19.
Sung C.
A Randomized, Placebo-Controlled Trial of Celgosivir in Dengue Fever Patients.
Rise in Hematocrit %
Fall in Platelet count x 1000 / mm3
PLoS Negl Trop Dis. 2016; 10: e0004851.
„ … celgosivir activity in treating dengue fever based on hematological endpoints.”
Stevens DR, Sawinski D, Blumberg E, Galanakis N, Bloom RD, Trofe-Clark J.
Increased risk of breakthrough infection among cytomegalovirus donor-positive/recipientnegative kidney transplant recipients receiving LD lower-dose valganciclovir prophylaxis.
Transpl Infect Dis. 2015; 17: 163-73.
Fauci AS.
Cyclophosphamide therapy of severe systemic necrotizing vasculitis.
N Engl J Med. 1979; 301: 235-8.
Rasche FM.
Cyclophosphamide pulse therapy in advanced progressive IgA nephropathy.
Nephron Clin Pract. 2003; 93: c131-6.
Kidney Dysfunction
vs
cell count nadir
Cyclophosphamie: Balance between efficacy and toxicity
Survival without Death
from vasculitis
from infection
Sellier-Leclerc AL.
Rituximab in steroid-dependent idiopathic nephrotic syndrome in childhood-follow-up after CD19 recovery.
Nephrol Dial Transplant. 2012; 27: 1083-9.
□ with CD19 B-cell suppression
CD19 recovery
Nephrotic syndrome
YES
NO
Relaps
Mélet J.
Rituximab-induced T cell depletion in patients with rheumatoid arthritis: association with clinical response.
Arthritis Rheum. 2013; 65: 2783-90.
T cell
CD3+
Response
= T cell depletion
CD4+
CD8+
ARC Response
NO
?
YES
Moreso F.
Incidence of leukopenia and cytomegalovirus
disease in kidney transplants treated with
mycophenolate mofetil combined with low
cyclosporine and steroid doses.
Clin Transplant. 1998; 12: 198-205.
„ … Patients receiving MMF showed a low incidence of biopsy proven rejection …
... All patients … who presented leukopenia recovered after MMF reduction dose … „
Leukocyte count
Titration curve
Conclusion:
Titration Dose !
← Dose
Standard or high
normal Dose
NO
Leukopenia
Continue previous Dose
YES
Decrease Dose
Candidates:
… cyclophosphamide, adriamycin/ doxorubicin, cisplatin, carboplatin, trifluridine … celgosivir,
valganciclovir … rituximab, mycophenolate … … azathioprine, lenalidomide …