Professional Documents
Culture Documents
How I Treat Paroxysmal Nocturnal Hemoglobinuria
How I Treat Paroxysmal Nocturnal Hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal, complement-mediated hemolytic anemia with protean
manifestations. PNH can present as a hemolytic anemia, a form of bone marrow failure, a thrombophilia, or any
1304 blood® 11 MARCH 2021 | VOLUME 137, NUMBER 10 © 2021 by The American Society of Hematology
Neisseria meningitides and started on eculizumab. Following the Patient 2: a 44-year-old man with
standard eculizumab introduction period (600 mg intravenously,
weekly), she was maintained on 900 mg intravenously (biweekly). classical PNH
Her dyspnea and abdominal pain resolved, and her warfarin was This 44-year-old man presents with a chief complaint of bright
discontinued after 3 months of anticoagulation. Repeat blood red hemoglobinuria, fatigue, chest pain, dyspnea on exertion,
counts revealed a hemoglobin level of 9.7 g/dL, 7.0% reticu- and difficulty swallowing liquids and solids after mowing his lawn
locytes, and an LDH of 271 IU/L. on a hot summer day. Complete blood count reveals a he-
moglobin of 6.7 g/dL, leukocytes of 3.8 3 10 9/L, platelets of
98 3 109/L, and an absolute reticulocyte count of 287 000 mm3.
Comments about patient 1 LDH level is 2800 IU/L. A direct antiglobulin test is negative. He
This patient illustrates the devastating complement-dependent reports reddish-dark urine in the morning most days of the week,
thrombophilia associated with PNH. It also highlights that not all a dull backache, and transient impotence. He had required
patients with PNH present with hemoglobinuria.20 The diagnosis 6 units of packed red cells in the past month to maintain a
was established by documenting the presence of a hemolytic hemoglobin greater than 7.5 g/dL. PNH flow cytometry reveals
anemia in conjunction with severe deficiency of GPI-anchored 18% PNH erythrocytes, 85% PNH granulocytes, and 87% PNH
HOW I TREAT PAROXYSMAL NOCTURNAL HEMOGLOBINURIA blood® 11 MARCH 2021 | VOLUME 137, NUMBER 10 1305
A Hemolysis in untreated PNH B PNH treated with C5 inhibition
Membrane Attack Complex
C5 convertase C5b-9
C5
C3b
C3b
C Pharmacokinetic D Pharmacodynamic
breakthrough hemolysis breakthrough hemolysis
Free C5
Opsonized red cells are phagocytosed
and undergo extravascular hemolysis
in the reticuloendothelial system
Time
Dosing
interval
Figure 1. Mechanisms of hemolysis in PNH. (A) Loss of CD55 and CD59 on PNH red cells leaves them vulnerable to complement-mediated intravascular hemolysis. (B) PNH red
cells from patients with PNH treated with C5 inhibition (eculizumab or ravulizumab) often become coated with C3 fragments that serve as opsonins and lead to extravascular
hemolysis in the spleen and liver. C5 inhibition compensates for the loss of CD59 and prevents intravascular hemolysis; however, CD55, upstream to C5 is important for accelerating
decay of the C3 convertase. The lack of CD55 from PNH red cells leads to the accumulation of C3b and its processed forms iC3b and C3dg. (C) Pharmacokinetic intravascular
hemolysis caused by insufficient drug dosing allows free C5 levels to rise. (D) Pharmacodynamic intravascular hemolysis. Complement amplifying conditions (pregnancy, infection,
major surgery) can result in excess C3b accumulation on PNH red cells that leads to a conformational change in C5 and decrease the binding of eculizumab or ravulizumab to C5,
resulting in breakthrough hemolysis even in the absence of a rise in free C5.
breakthrough tends to occur regularly and usually 10 days or between doses; switching to ravulizumab is also effective and
more after the last dose of drug, as is happening with patient 3. more convenient for the patient.
Pharmacodynamic breakthrough occurs despite adequate drug
levels. Under strong complement activation (third trimester Pharmacokinetic breakthrough hemolysis abated after ravulizumab,
pregnancy, infection, major surgery etc) PNH red cells densely but patient 2, like virtually all patients treated with eculizumab
coated with C3b can cause C5 to adopt a C5b-like conformation and ravulizumab, continues to experience extravascular hemo-
that is not inhibited by eculizumab or ravulizumab.35 In the 2 lysis and a mild to moderate anemia. PNH red cells are deficient
largest clinical trials of ravulizumab, no breakthrough hemolysis in CD59, which inhibits formation of the membrane attack
was associated with elevations in free C5 levels (pharmacokinetic complex. They are also deficient in CD55, which inhibits the C3
breakthrough).29 Pharmacokinetic breakthrough hemolysis was and C5 convertases. Ravulizumab binds to C5 and inhibits the C5
less frequent with ravulizumab compared with eculizumab. convertase (C3bBbC3b×P) from cleaving C5 into C5a and C5b. It
There was no difference in pharmacodynamics breakthrough inhibits complement upstream of CD59 and decreases in-
between the 2 drugs. Pharmacokinetic breakthrough responds travascular hemolysis by preventing formation of the membrane
to increasing the dose of eculizumab or shortening the interval in attack complex.36 CD55 is upstream of C5. Patients with PNH on
HOW I TREAT PAROXYSMAL NOCTURNAL HEMOGLOBINURIA blood® 11 MARCH 2021 | VOLUME 137, NUMBER 10 1307
Comments about patient 4 Next-generation complement inhibitors
Small clinically silent PNH clones are found in up to 70% of adults
and 10% of children with acquired aplastic anemia. It is im-
for PNH
portant to screen all aplastic anemia for the presence of PNH Eculizumab and ravulizumab prevent intravascular hemolysis
cells. First, it helps exclude the inherited forms of bone marrow and prevent thrombosis (the leading cause of death) in the
failure (ie, Fanconi anemia, dyskeratosis congenita) as PNH is natural history of PNH; however, there is room for improvement.
almost never associated with inherited forms of bone marrow More than 50% of patients with PNH on C5 inhibitors have mild
failure.6 Second, some patients (patient 4) can present with an to moderate symptoms from PNH, and up to 20% still need
overlap syndrome of PNH and aplastic anemia. In these cases, occasional transfusions. The most common reason for continued
definitive therapy is directed at the aplastic anemia, but in rare anemia is extravascular hemolysis (patient 2). New complement
cases, as above, the PNH clone also needs to be addressed. This inhibitors50 are being developed to treat PNH, and several may
patient meets criteria for severe aplastic anemia; thus, allogeneic become FDA approved in the next year or two. Pegcetacoplan is
BMT is indicated and has the potential to eradicate both the a C3 inhibitor that is administered subcutaneously, twice weekly,
aplastic anemia and the PNH clone.44,45 Eculizumab was ad- and is capable of blocking both intravascular and extravascular
ministered in this case to treat the potentially life-threatening hemolysis. The drug is being compared head-to-head with
Authorship
Final considerations and future directions Contribution: R.A.B. wrote the paper.
REFERENCES 6. DeZern AE, Symons HJ, Resar LS, Borowitz nocturnal hemoglobinuria (PNH). Blood.
MJ, Armanios MY, Brodsky RA. Detection of 2006;108(13):4232-4236.
1. Hill A, DeZern AE, Kinoshita T, Brodsky RA.
paroxysmal nocturnal hemoglobinuria clones
Paroxysmal nocturnal haemoglobinuria. Nat 10. Hillmen P, Young NS, Schubert J, et al.
to exclude inherited bone marrow failure
Rev Dis Primers. 2017;3(1):17028. The complement inhibitor eculizumab in
syndromes. Eur J Haematol. 2014;92(6):
2. Luzzatto L. PNH phenotypes and their genesis. 467-470. paroxysmal nocturnal hemoglobinuria.
Br J Haematol. 2020;189(5):802-805. N Engl J Med. 2006;355(12):1233-1243.
7. Shen W, Clemente MJ, Hosono N, et al. Deep
3. Kinoshita T, Fujita M. Biosynthesis of GPI- sequencing reveals stepwise mutation acqui- 11. Brodsky RA, Young NS, Antonioli E, et al.
anchored proteins: special emphasis on GPI sition in paroxysmal nocturnal hemoglobin- Multicenter phase 3 study of the complement
lipid remodeling. J Lipid Res. 2016;57(1):6-24. uria. J Clin Invest. 2014;124(10):4529-4538. inhibitor eculizumab for the treatment of pa-
tients with paroxysmal nocturnal hemoglo-
4. Luzzatto L, Bessler M, Rotoli B. Somatic mu- binuria. Blood. 2008;111(4):1840-1847.
tations in paroxysmal nocturnal hemoglobin- 8. Fraiman YS, Cuka N, Batista D, Vuica-Ross M,
uria: a blessing in disguise? Cell. 1997;88(1): Moliterno AR. Development of paroxysmal 12. Lee JW, Sicre de Fontbrune F, Wong Lee Lee
1-4. nocturnal hemoglobinuria in CALR-positive L, et al. Ravulizumab (ALXN1210) vs eculizu-
myeloproliferative neoplasm. J Blood Med. mab in adult patients with PNH naive to
5. Yuan X, Braunstein EM, Ye Z, et al. Generation 2016;7:107-110. complement inhibitors: the 301 study. Blood.
of glycosylphosphatidylinositol anchor 2019;133(6):530-539.
protein-deficient blood cells from human in- 9. Inoue N, Izui-Sarumaru T, Murakami Y, et al.
duced pluripotent stem cells. Stem Cells Molecular basis of clonal expansion of he- 13. Kulasekararaj AG, Hill A, Rottinghaus ST, et al.
Transl Med. 2013;2(11):819-829. matopoiesis in 2 patients with paroxysmal Ravulizumab (ALXN1210) vs eculizumab in
HOW I TREAT PAROXYSMAL NOCTURNAL HEMOGLOBINURIA blood® 11 MARCH 2021 | VOLUME 137, NUMBER 10 1309