Page 1303 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 70 Primary Myelofibrosis 1149

How Should PMF Patients With Thrombocytopenia Be Treated?—cont’d

in other JAK2 inhibitor clinical trials in which reduced platelet counts are with steroids. About 20–30% of patients with severe thrombocytopenia
acceptable (such as the PERSIST-2 phase III pacritinib trial) or in clinical will have significant improvement in platelet counts after a splenectomy.
trials with other agents in development. If thrombocytopenia worsens with Aggressive platelet transfusional support is necessary before, during,
the current treatment plan, then proceed with the strategy outlined below. and after splenectomy in many cases. However, splenectomy in patients
with PMF is associated with a postoperative morbidity rate of 15–30%
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Platelet Count 20–50 × 10 /L: and a mortality rate close to 10%. These numbers, however, are highly
Thalidomide or lenalidomide in combination with prednisone can be dependent on the institutional experience and the operating surgeon.
used to correct anemia in these PMF patients but rarely improve the Splenectomy can also result in extramedullary hematopoiesis in the liver,
platelet counts in a clinically meaningful way. Most clinical trials involving causing hepatomegaly, which may require the administration of judicious
a variety of therapeutic agents including JAK2 inhibitors will require amount of chemotherapeutic agents (hydroxyurea, busulfan, cladribine)
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baseline platelets above 50 × 10 /L. In patients who are experiencing or a JAK2 inhibitor. Severe thrombocytopenia is an adverse prognostic
life-threatening bleeding, in addition to aggressive immediate platelet feature. Such patients who are eligible for stem cell transplantation (SCT)
transfusions, splenectomy is a reasonable therapeutic option. and have available donors should be considered for transplantation.
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Platelet Count <20 × 10 /L Thrombopoietin mimetics have been associated with increased bone
The treatment choices are truly limited for these patients. Intervention marrow fibrosis when used for the treatment of immune thrombocytopenia
purpura and have not been evaluated in the setting of PMF-associated
is also dependent on the clinical picture, with emphasis on addressing thrombocytopenia. Additionally, patients with extreme thrombocytopenia
bleeding. Supportive therapy with frequent platelet transfusions is a pos- and signs of leukemic transformation can be considered for therapy with
sibility, but it is likely not sustainable in the long term. It is our practice to decitabine or azacytidine with aggressive platelet transfusional support,
transfuse if the platelet count is below 10 × 10 /L unless there is no evi- and then ideally should proceed to allogeneic SCT if a donor is available
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dence of mucosal bleeding or life-threatening hemorrhage. Occasionally, and the patient’s performance status is appropriate.
patients may have an improvement in the degree of thrombocytopenia
Which Patients Should Be Considered for Allogeneic Hematopoietic Stem Cell Transplantation?
Allogeneic stem cell transplantation (aSCT) is the only potential curative donors should consider transplantation before developing debilitating
treatment option for primary myelofibrosis (PMF). Patients with poor risk symptoms or significant worsening in their performance status. Patients
features and decreased probability for survival should be considered for with low-risk disease can be closely monitored without intervention but
SCT because of the not insignificant risk of transplant-related morbidity should proceed to transplantation with evidence of disease progression.
and mortality. All patients younger than 70 years of age and their siblings For patients with available donors but poor performance status because
should be human leukocyte antigen typed at the time of diagnosis to of symptoms of myelofibrosis, a course of treatment with ruxolitinib
determine if there is a potential match. Patients between the ages of 65 can be considered with a goal of improvement in performance status
and 70 years with available related donors should be evaluated based on associated with reduction of splenomegaly and constitutional symptoms.
their performance status and presence of comorbid conditions. Patients These patients may become more viable transplant candidates with
younger than 70 years of age with good performance status and available this pretransplant treatment approach. Splenectomy before transplant
donors (either related or fully matched unrelated) should be encouraged to is not essential to ensure adequate engraftment. Currently, SCT using
undergo evaluation for SCT soon after the diagnosis and preferably within a reduced-intensity conditioning regimens, haploidentical donors, and cord
clinical trial. Patients with high- or intermediate-risk disease with available blood grafts are being actively evaluated.

Which PMF Patients Are Appropriate for JAK2 Inhibitor Therapy?

Not all primary myelofibrosis (PMF) patients require treatment with JAK2 cell transplantation (SCT) as a means to improve their performance status
inhibitor therapy. Patients with symptomatic splenomegaly or debilitating and promote weight gain in an attempt to optimize them for SCT, is under
myelofibrosis (MF)-related symptoms are potential candidates for treat- prospective evaluation within the MPD-Research Consortium. Although
ment with ruxolitinib. Inhibition of JAK1/2 is associated with myelosup- the COMFORT 1 trial reported a modest improvement in survival at a
pression and could further compromise existing cytopenias. In patients median of 51 weeks of treatment with ruxolitinib, the exact mechanism
with isolated splenomegaly and adequate blood counts, a course of that underlies this survival benefit remains, and this agent should not
hydroxyurea should be considered. If the patient fails hydroxyurea or has be given with the primary goal of disease process modification and
debilitating symptoms, then ruxolitinib would be the appropriate agent. promoting increased survival. Patients started on ruxolitinib need to have
Ruxolitinib is currently approved for patients with intermediate- and high- frequent monitoring of blood counts, and if discontinued, the dose should
risk MF, and has yet to be explored in cases of symptomatic patients with be either tapered or a pulse of concurrent steroid therapy considered to
low-risk disease. Additionally, the use of this drug is not advised in MF avoid the rapid reappearance of systemic symptoms and splenomegaly,
patients with platelet counts below 50 × 10 /L. Whether Ruxolitinib should which can occur at times.
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be used in patients with poor performance status before allogeneic stem

How Does Characterizing the Mutational Profile of a PMF Patient Influence Care?

Assessing the status of the primary myelofibrosis driver mutations JAK2, have recently been proposed but not yet validated in prospective trials. It
MPL, and CALR can help refine prognostication and influence therapeu- is also important to remember that JAK2 wild type status, and MPL- and
tic decision-making. Retrospective studies suggest that molecular risk CALR-mutated patients respond equally well to ruxolitinib therapy. The
stratification can further refine the individual risk for leukemic transforma- characterization of nearly 20 recurrent gene mutations in PMF patients
tion and shortened overall survival. Patients with triple-negative status has been reported by various groups and implicates a complex and
(lacking mutations of JAK2, MPL, and CALR) or with an ASXL1 mutation heterogeneous molecular pathophysiology that will likely not allow for a
are at highest risk for a poor outcome and should be evaluated for early single therapeutic target drug approach. Whether the presence of certain
stem cell transplantation (SCT) or experimental therapy, even if they gene mutations will ultimately predict for therapeutic response with dif-
are assessed to have low-risk disease by conventional risk-stratification fering agents has yet to be shown. The presence of these mutations can
tools. Such patients should be sent for transplant at the earliest time of also be used to detect minimal residual disease after SCT
evidence of disease evolution. Proposed molecular stratification tools