Primary Myelofibrosis

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Chapter 30 Primary Myelofibrosis

John Mascarenhas, Vesna Najfeld, Marina Kremyanskaya, Ronald Hoffman

Figure 30-1 Survival of patients with myelofibrosis after reduced-intensity allogeneic stem cell transplantation according to age (A), donor (B), and Lille risk profile (C).

Algorithm for Selection of Appropriate Patients for Stem Cell Transplantation Stratified According to Risk Status

Case Vignettes

How Should PMF Patients with Thrombocytopenia Be Treated?

Which Patients Should Be Considered for Allogeneic Stem Cell Transplantation?

Allogeneic SCT is the only potential curative treatment option for PMF. Patients with poor risk features and decreased probability for survival should be considered for SCT because of the not insignificant risk of transplant related morbidity and mortality. All patients younger than 70 years of age and their siblings should be HLA typed at the time of diagnosis to determine if there is a potential match. Patients between the ages of 65 and 70 years with available related donors should be evaluated based on their performance status and comorbid conditions. Patients younger than 65 years with good performance status and available donors (either related or fully matched unrelated) should be encouraged to undergo evaluation for SCT soon after the diagnosis and preferably within a clinical trial. Patients with high- or intermediate-risk disease with available donors should consider transplantation before developing debilitating symptoms or significant worsening in their performance status. Patients with low-risk disease should be closely monitored without intervention but should proceed to transplantation with evidence of disease progression. For patients with available donors but poor performance status because of symptoms of MF, a course of treatment with ruxolitinib can be considered with a goal of improvement in performance status associated with reduction of splenomegaly and constitutional symptoms. These patients may become more viable transplant candidates with this pretransplant treatment approach. Splenectomy before transplant is not essential to ensure adequate engraftment. Currently, SCT using RCI regimens, haploidentical donors, and cord blood grafts are being evaluated.

Which PMF Patients Are Appropriate for JAK2 Inhibitor Therapy???

Not all patients require treatment with JAK2 inhibitor therapy. Patients with symptomatic splenomegaly or debilitating MF-related symptoms are potential candidates for treatment with ruxolitinib. Inhibition of JAK1/2 is associated with myelosuppression and could further compromise existing cytopenias. In patients with splenomegaly and constitutional symptoms with adequate blood counts, a course of hydroxyurea should be considered. If the patient fails hydroxyurea or has debilitating symptoms, then ruxolitinib would be the appropriate agent. Ruxolitinib is currently approved for patients with intermediate- and high-risk MF and has yet to be explored in cases of symptomatic patients with low-risk disease. Additionally, this drug has not yet been fully evaluated in MF patients with platelet counts below 100 × 10⁹/L. Ruxolitinib could also be used in patients with poor performance status before allogeneic SCT as a means to improve their performance status and promote weight gain in an attempt to optimize them for SCT. Although the COMFORT 1 trial reported a modest improvement in survival at a median of 51 weeks of treatment with ruxolitinib, the exact mechanism that would provide for this survival benefit is not yet understood, and this agent should not be given with the primary goal of disease process modification and increased survival. Patients started on ruxolitinib need to have frequent monitoring of blood counts, and if discontinued, the dose should be either tapered or a pulse of steroid therapy considered to avoid the rapid reappearance of systemic symptoms and splenomegaly.

Table 30-1 Conditions Associated With Myelofibrosis

MALIGNANT DISORDERS

Table 30-2 Summary of Symptoms and Physical Findings of Patients With Primary Myelofibrosis Detected at Diagnosis

Figure 30-2 PRIMARY MYELOFIBROSIS (PMF).

Peripheral blood and bone marrow (BM) biopsy. The leukocyte count can vary in PMF from leukopenia to marked leukocytosis. In the case illustrated, the count was normal (A). However, the smear showed numerous dacryocytes, or teardrop forms (B), and a leukoerythroblastic picture (C to E), that is the presence leukoblasts, or immature granulocytic precursors (C), including myeloblasts (D), and circulating nucleated red blood cells or erythroblasts (E). The BM biopsy is frequently hypercellular (F) and comprised of an atypical megakaryocytic and granulocytic proliferation (G) in which some of the megakaryocytes have atypical and pyknotic nuclei. Other megakaryocytes (H) are considered to have nuclei that are “cloudlike.” The BM biopsy frequently shows sinusoidal hematopoiesis (I) and significant fibrosis as illustrated by a reticulin stain (J).

Figure 30-3 DIFFERENTIAL DIAGNOSTIC CONSIDERATIONS IN PRIMARY MYELOFIBROSIS (PMF).

A to E, Acute panmyelosis with myelofibrosis (APMF). F and G, Chronic myelogenous leukemia (CML) in an advance phase with fibrosis. H and I, Myelodysplastic syndrome (MDS) with fibrosis. The bone marrow (BM) biopsy of APMF, CML in advanced phase with fibrosis, and MDS with fibrosis can all look similar to PMF at low power (A, F, and H). In APMF, the distinction from PMF is made in part by seeing increased immature cells on the biopsy (B) interspersed with other hematopoietic precursors. These are usually CD34⁺ (C) but in contrast to acute megakaryoblastic leukemia are usually CD61 negative (D). Also, the peripheral blood usually shows pancytopenia with neither teardrop red blood cells nor a leukoerythroblastosis (E). Although the biopsy of CML presenting in an advanced phase can resemble PMF (F), the peripheral blood usually shows a classic granulocytosis with left shift and basophilia (G). In the case illustrated, the 30-year-old female patient had fibrotic BM (F) but presented with a white blood cell count of 148,000/L showing a full spectrum of granulocytes, increased blasts (22%), and basophilia. P210 BCR/ABL1 was demonstrated. The bone marrow biopsy in MDS with fibrosis has small megakaryocytes (H), but dysplasia is otherwise difficult to evaluate in the absence of an aspirate, and one must rely on the peripheral blood to identify dysplasia, as in the severely dysplastic neutrophil (F).

Table 30-3 Proposed Revised World Health Organization Criteria for Primary Myelofibrosis *

MAJOR CRITERIA

1. Presence of megakaryocyte proliferation and atypia,^† usually accompanied by either reticulin or collagen fibrosis, or, in the absence of significant reticulin fibrosis, the megakaryocyte changes must be accompanied by an increased bone marrow cellularity characterized by granulocytic proliferation and often decreased erythropoiesis (i.e., prefibrotic cellular-phase disease)

2. Not meeting WHO criteria for PV,^‡ CML,^§ MDS,^‖ or other myeloid neoplasm

3. Demonstration of JAK2617V >F or other clonal marker (e.g., MPL515W >L/K) or in the absence of a clonal marker, no evidence of bone marrow fibrosis caused by underlying inflammatory or other neoplastic diseases ^¶

MINOR CRITERIA

1. Leukoerythroblastosis **

2. Increase in serum lactate dehydrogenase level **

3. Anemia **

4. Palpable splenomegaly **

CML, Chronic myeloid leukemia; MDS, myelodysplastic syndrome; PV, polycythemia vera; WHO, World Health Organization.

^*Diagnosis requires meeting all three major criteria and two minor criteria.

^†Small to large megakaryocytes with an aberrant nuclear-to-cytoplasmic ratio and hyperchromatic, bulbous, or irregularly folded nuclei and dense clustering.

^‡Requires the failure of iron replacement therapy to increase hemoglobin level to the polycythemia vera range in the presence of decreased serum ferritin. Exclusion of polycythemia vera is based on hemoglobin and hematocrit levels. Red blood cell mass measurement is not required.

^§Requires the absence of BCR-ABL.

^‖Requires the absence of dyserythropoiesis and dysgranulopoiesis.

^¶Secondary to infection, autoimmune disorder or other chronic inflammatory condition, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies. It should be noted that patients with conditions associated with reactive myelofibrosis are not immune to primary myelofibrosis, and the diagnosis should be considered in such cases if other criteria are met.

^**Degree of abnormality could be borderline or marked.

Data from Tefferi A, Thiele J, Orazi A, et al: Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: Recommendations from an ad hoc international expert panel, Blood 110:1092, 2007.

Figure 30-4 OVERALL SURVIVAL FROM THE TIME OF DIAGNOSIS OF 141 PATIENTS WITH PRIMARY MYELOFIBROSIS.

(Data from Silverstein MN: Agnogenic myeloid metaplasia, Acton, MA, 1975, Publishing Sciences Group, p 197.)

Figure 30-5 MODELS TO EXPLAIN PROGRESSION FROM A JANUS KINASE 2 (JAK2) MUTANT MYELOPROLIFERATIVE NEOPLASM TO A JAK2 WILD-TYPE LEUKEMIA.

In model 1 (i), the two phases of disease are phylogenetically related, having arisen from a shared (pre-JAK2) founder clone, but in model 2 (ii), the two phases of disease are clonally unrelated, reflecting transformation of independent stem cells. AML, acute myeloid leukemia; HSC, hematopoietic stem cell.

(From Beer PA, Delhommeau F, LeCouédic JP, et al: Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood 115:2891, 2010.)

Figure 30-6 REDUCTION IN SPLENIC VOLUME WITH RUXOLITINIB THERAPY IN THE COMFORT 2 TRIAL.

The waterfall plot shows the percent change from baseline in spleen volume at week 24 (in 139 patients in the ruxolitinib group and 106 in the placebo group) or at the last evaluation before week 24 (in 16 patients in the ruxolitinib group and 47 in the placebo group). Data for one patient with a missing baseline value are not included on the graph. Most patients in the ruxolitinib group (150 of 155) had a reduction in spleen volume, but most patients in the placebo group had either an increase in spleen volume (102 of 153 patients) or no change (15 of 153 patients).

(Data from Verstovsek S, Mesa RA, Gotlib J, et al: A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 366:799, 2012.)