Page 1356 - Williams Hematology ( PDFDrive )

1330 Part X: Malignant Myeloid Diseases Chapter 86: Primary Myelofibrosis 1331

Patients engraft at a rate similar to the rate of patients with hemato- (<4.0 × 10 /L); (4) constitutional symptoms of fever, sweating, or weight
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logic diseases without marrow fibrosis (Chap. 23). The decision to use loss at the time of diagnosis; (5) proportion of blast cells in the blood
full-conditioning allogeneic transplantation is a function of the patient’s (≥1 percent); (6) male gender; (7) severity of thrombocytopenia; (8)
age (<50 years), the severity of the blood cell and marrow abnor- proportion of CD34+ cells in the blood; (9) the presence of the V617F
malities, and the likelihood of a protracted indolent course without mutation in JAK2; (10) monocytosis; (11) a decreased proliferating
transplantation. Younger patients, especially those younger than age cell nuclear antigen index and a decreased apoptotic index by in situ
50 years, with a DNA-based matched sibling donor, progressive disease, end labeling; (12) degree of liver enlargement; (13) extent of marrow
and poor prognostic findings, such as hemoglobin less than 10 g/dL, fibrosis; (14) postsplenectomy spleen histology; (15) WT1 expression
blast cells greater than 1 percent of blood cells, unfavorable cytogenet- in CD34+ cells; and (16) certain clonal cytogenetic abnormalities, espe-
ics (e.g., abnormalities involving chromosome 5, 7, or 17, or cells with cially involving chromosome 5, 7, or 17, or with three or more abnor-
three or more abnormalities) are usually considered for transplantation. malities. Abnormalities such as 13q or 20q did not affect patient survival
Although a large spleen may slightly delay the expression of donor gran- compared to those patients without cytogenetic alterations.
ulopoiesis, on average the results in patients with a spleen is the same as Each retrospective study has found a different subset of these fac-
those who had prior splenectomy. 471,474 In addition, the latter procedure tors to be significant prognostic factors. The most consistent predictive
incurs significant risk of morbidity or mortality. variables appear to be advanced age, severity of anemia, and higher-risk
Patients younger than age 50 years who are transplanted with clonal cytogenetic abnormality at the time of diagnosis, each of which
stem cells from a matched sibling donor have a lower posttransplan- represents a poor prognostic indicator. 8,12,14,16,312,314,485–490
tation mortality and have better outcomes than those older than age In a study of more than 1000 consecutive cases of myelofibrosis
460
50 years. Transplant-related mortality using full-conditioning regi- at seven centers, among which the median survival was 69 months,
mens is approximately 35 to 40 percent and 5-year survival is approxi- variables (1) through (5) (listed above) proved to be the most useful in
mately 50 percent in patients younger than 50 years of age. dividing patients into four risk-factor categories. Shorter survival was
Donor lymphocyte infusion in patients who have lost donor dom- observed in patients who were older than age 65 years, had a hemo-
inance of hematopoiesis and a return of myelofibrosis can result in globin concentration less than 10 g/dL, a leukocyte count greater than
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regression of fibrosis and return to normal hematopoiesis for at least 25 × 10 /L (25,000/μL), a blood blast cell count equal to or greater than
6 and 20 months at the time of reporting. 475,476 1 percent, and constitutional symptoms. The patients were assigned
In JAK2 V617F -positive patients, real-time polymerase chain reaction to a risk group based on the number of risk factors present. If no risk
analysis can permit a sensitive determination of residual JAK2 V617F - factors were present, risk was low; if one factor was present, risk was
positive cells after transplantation. In a study of patients receiving low-intermediate; if two risk factors were present, risk was high-
low-intensity conditioning, 17 of 21 patients became JAK2 V617F -negative, intermediate; and if three or more risk factors were present, risk was high.
and in one case donor lymphocyte infusion eliminated JAK2 V617F -posi- The application of these variables could distinguish among patients with
tive cells. 477 low risk with a survival of 135 months, low-intermediate risk with a sur-
The option of nonmyeloablative transplantation in older patients vival of 95 months, high-intermediate risk with a survival of 48 months,
is gaining favor. 470,471,478–482 Several reports of lower posttransplanta- and high risk with a survival of 27 months. Overall, the 5-year survival
491
tion mortality and salutary outcomes have led some to consider this of patients with primary myelofibrosis is approximately 40 percent of the
approach as the preferred approach in patients older than 50 years of survival expected for healthy age- and sex-matched controls. 492
age, and perhaps in younger patients as well. One study showed that Some data suggest that the use of JAK2 inhibitors in the treat-
the outcome of nonmyeloablative transplantation was dramatically bet- ment of primary fibrosis may not only decrease symptomatology and
470
ter than myeloablative transplant. The study compared 17 patients spleen size, but may prolong survival. 493,494 An analysis of 100 patients
receiving a myeloablative conditioning regimen and 10 receiving non- receiving ruxolitinib compared to 350 carefully matched patients who
myeloablative conditioning. The median age was 50 years (age range: did not receive ruxolitinib showed a median 18-month prolongation in
5 to 63 years) at transplantation. After a median followup of 55 months, survival in patients with poorer prognosis disease. At the upper range
20 patients were alive. The transplantation-related mortality was 10 per- some patients had a 4- to 5-year prolongation of life. In addition, the
494
cent in the nonmyeloablative group and 30 percent in the myeloablative clinical improvement in vitality and functionality can be dramatic.
group. There was no difference in survival for high- or low-risk patients The major causes of death are infection, hemorrhage, postsple-
or between sibling and unrelated donor transplantations. This study nectomy mortality, and acute leukemic transformation. 495–499 Acute
confirmed prior smaller comparisons of myeloablative and nonmye- leukemia occasionally is preceded by the development of myeloid sar-
loablative stem cell transplantation. 483 comas. 35,460,499,500 Evolution of the disease to acute lymphocytic leukemia
A large cooperative study of reduced conditioning transplantation or lymphoma may occur. 501,502 An increased risk of progression to leu-
503
found the most favorable results in transplants using matched-related kemia has been reported in splenectomized patients. Progression to
donors and in intermediate stage disease. 482 acute leukemia is associated with a blast count greater than 3 percent
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Autologous blood stem cells mobilized with granulocyte colony- and a platelet count less than 100,000/μL (100 × 10 /L) at the time of
stimulating factor (G-CSF) and administered after busulfan condi- diagnosis. Treatment with erythropoietin or androgens is associated
504
tioning produced clinical benefit, including improved erythropoiesis, with increased risk of progression to acute leukemia, as well. The
improved platelet counts, and decreased splenic size, in a plurality of administration of JAK2 inhibitors may provide improved efficacy for
21 patients with primary myelofibrosis whose age range was 45 to the treatment of AML evolving in patients with primary myelofibro-
75 years. The 2-year actuarial survival rate was 61 percent. 484 sis. Rare spontaneous remissions of apparent primary myelofibrosis are
documented. 505,506
COURSE AND PROGNOSIS A variety of gene mutations have been associated with prognosis
in patients with primary myelofibrosis, either overall survival or risk of
The rate of disease progression is associated with at least 16 variables conversion to acute myelogenous leukemia. These include the follow-
measured at the time of diagnosis, namely: (1) older age; (2) severity ing gene mutations: IDH, EZH, ASXLI, and SRSF2. 507,508 The A3669G
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of anemia; (3) exaggerated leukocytosis (>25 × 10 /L) or leukopenia (rs6198) single nucleotide polymorphism of the glucocorticoid receptor

Kaushansky_chapter 86_p1319-1340.indd 1331 9/18/15 10:24 AM