RT Book, Section
A1 Tashi, Tsewang
A1 Prchal, Jaroslav F.
A1 Prchal, Josef T.
A2 Kaushansky, Kenneth
A2 Prchal, Josef T.
A2 Burns, Linda J.
A2 Lichtman, Marshall A.
A2 Levi, Marcel
A2 Linch, David C.
SR Print(0)
ID 1180472711
T1 Polycythemia Vera
T2 Williams Hematology, 10e
YR 2021
FD 2021
PB McGraw-Hill Education
PP New York, NY
SN 9781260464122
LK accessmedicine.mhmedical.com/content.aspx?aid=1180472711
RD 2024/04/18
AB SUMMARYPolycythemia  vera  (PV)  is  classified  in  the  group  of  Philadelphia  chromosome–negative  myeloproliferative  neoplasms  (MPN)  that  also  includes  essential  thrombocythemia  (ET)  and  primary  myelofibrosis  (PMF).  PV  is  an  acquired  primary  clonal  disorder.  Primary  polycythemias  result  from  abnormal  intrinsic  properties  of  erythroid  progenitors  that  proliferate  independently  (or  excessively)  of  extrinsic  regulators  such  as  erythropoietin;  low  serum  erythropoietin  is  their  hallmark.  It  arises  from  mutation(s)  of  a  pluripotent  hematopoietic  stem  cell,  which  results  in  excess  production  of  erythrocytes  and  variable  overproduction  of  granulocytes  and  platelets.  It  is  often  accompanied  by  splenomegaly.  Almost  all  patients  with  PV  have  a  somatic  mutation  of  the  Janus-type  tyrosine  kinase-2  gene  (JAK2)  that  is  detectable  in  blood  myeloid  cells.  The  mutation  results  in  constitutive  hyperactivity  of  JAK2  kinase  stemming  from  loss-of-function  of  its  negative  regulatory  domain.  The  most  common  mutation  is  JAK2,V617F  which  is  present  in  the  vast  majority  of  cases;  a  small  minority  of  patients  with  PV  have  a  mutation  in  other  parts  of  JAK2  (exon  12).  The  JAK2V617F  mutation  is  also  found  in  many  patients  with  ET  and  PMF,  albeit  at  lower  frequency;  55%  in  ET  and  65%  in  PMF.  As  with  other  clonal  hematologic  disorders,  PV  can  undergo  a  clonal  evolution  to  PMF  (JAK2V617F-positive)  or  acute  leukemia  (either  JAK2V617F-negative  or  -positive).  In  virtually  all  JAK2V617F-positive  PV  patients,  at  least  some  progenitors  exist  that  become  homozygous  for  the  JAK2V617F  mutation  by  uniparental  disomy-acquired  mitotic  recombination.  The  majority  of  these  progenitors  account  for  the  erythropoietin-independent  erythroid  colonies  detected  in  vitro  by  clonogenic  burst-forming  unit–erythroid  assay  (BFU-E).  The  JAK2V617F  mutation  is  often  not  the  initial  cause  of  clonal  proliferation  but  may  be  preceded  by  other  germline  and  somatic  mutation(s)  (eg,  TET2).Arterial  and  venous  thromboses  are  a  major  cause  of  morbidity  and  mortality  in  PV,  and  a  smaller  proportion  of  patients  develop  secondary  myelofibrosis  (sometimes  called  the  spent  phase)  and/or  an  invariably  fatal  acute  leukemic  transformation.  Myelosuppressive  therapy  has  been  an  effective  mode  of  therapy,  with  drugs  such  as  hydroxyurea  (HU),  busulfan,  pipobroman,  and  radioactive  phosphorus  useful  in  controlling  proliferation  of  all  blood  cell  lineages  and  decreasing  the  incidence  of  thrombotic  complications.  In  contrast,  pegylated  interferon-α  may  lead  to  complete  hematologic  remission  and  restoration  of  polyclonal  hematopoiesis  in  some  patients.  Targeted  therapy  with  JAK2  kinase  inhibitors  has  been  found  effective  in  decreasing  the  need  for  phlebotomies,  decreasing  the  white  cell  count  and  splenomegaly,  and  improving  the  patient’s  quality  of  life,  without  selective  inhibition  of  the  PV  clone.