Anemia in myelophthisis: causes, diagnosis, treatment

Anemia in myelophthisis is a hypoproliferative anemia resulting from the displacement of normal bone marrow by non-physiological tissues: malignant cells (metastases from solid tumors, lymphomas), fibrosis, granulomas, or other infiltrates. Key laboratory findings include a leukoerythroblastic pattern in the peripheral blood (the simultaneous appearance of young granulocytes and normoblasts), "tearful" erythrocytes (dacryocytes), normochromic-normocytic anemia, and, as a rule, low reticulocytosis for the degree of anemia. This distinguishes myelophthisis from blood loss/hemolysis, where reticulocytes are usually elevated. [1]

Myelophthisis is a form of bone marrow failure: its cause is not stem cell failure, as in idiopathic aplastic anemia, but the "occupation" of bone marrow niches by foreign tissue or scar tissue. In practice, myelophthisis often debuts in cancer patients (breast, prostate, lung, etc.) with metastases to the bone marrow, but also occurs in primary hematological diseases, such as primary myelofibrosis. In response to the deficiency of hematopoietic tissue, extramedullary hematopoiesis (liver, spleen) is activated, which partially compensates for cytopenias. [2]

Two aspects are clinically important. First, myelophthisis is often associated with thrombocytopenia and/or neutropenia, making patients vulnerable to bleeding and infection. Second, there is the "sentinel smear" syndrome: the detection of leukoerythroblastosis and dacryocytes is a reason to urgently seek the cause of bone marrow infiltration and not limit ourselves to simply declaring "anemia of chronic disease." [3]

Early diagnosis determines the treatment strategy: in cases of tumor genesis, the primary tumor is treated (systemic therapy, hormonal therapy, radiation therapy); in cases of primary myelofibrosis, JAK/STAT pathway inhibitors (ryuxolitinib, fedratinib, pacritinib, momelotinib) are used; in cases of granulomatosis, etiotropic therapy is used. Supportive measures (transfusions, erythropoiesis-stimulating drugs in cancer patients when indicated, treatment of deficiencies) improve quality of life and help control the underlying cause. [4]

Code according to ICD-10 and ICD-11

ICD-10 provides a separate code for myelophthisis, D61.82 "Myelophthisis," which includes the synonyms "myelophthisic anemia," "leukoerythroblastic anemia," and "panmyelophthisis." It is important to also code the underlying disease (e.g., malignant tumor), since D61.82 reflects the bone marrow failure syndrome, but not its underlying cause. [5]

ICD-11 does not have a separate, narrowly defined category for "myelophthisis"; the practice is to use section 3A70 "Aplastic anemia" with clarifications for acquired forms - in particular, 3A70.1Y "Other specified acquired aplastic anemias" - with post-coordination of the underlying disease/condition (for example, "anemia in neoplasm" 3A71.0) in oncological genesis. A specific combination of codes is selected based on the clinical scenario and national medical coding guidelines. [6]

Table 1. Codes for myelophthisis

Position	ICD-10	ICD-11	Comments
Myelophthisis (myelophthisic anemia)	D61.82	3A70.1Y (other specified acquired aplastic anemias)	In ICD-11 the cause is specified (e.g. 3A71.0 “Anemia in malignant neoplasms”). [7]
Myelofibrosis (for differential coding)	D75.81	-	A separate nosology; can lead to myelophthisis. [8]
Anemia due to neoplasm	D63.0	3A71.0	They are coded simultaneously with the main oncodiagnosis. [9]

Epidemiology

Myelophthisic anemia is less common than "classic" anemia of chronic disease, but it should be actively sought in patients with advanced tumors. In retrospective series, myelophthisis has been observed in a minority of cancer patients: according to some observations, it occurs in "less than 10%" of patients with metastatic solid tumors (especially breast, lung, and prostate), which is consistent with the clinical experience of large centers. The actual incidence depends on the population and oncological profile. [10]

In hematological diseases, myelophthisis plays a significant role in primary myelofibrosis and other conditions associated with massive fibrotic bone marrow remodeling. In these patients, leukoerythroblastosis and dacryocytes are more common, and anemia is often associated with splenomegaly and extramedullary hematopoiesis. In cancer patients, myelophthisis often coexists with chemotherapy-induced and inflammatory anemia, complicating diagnosis. [11]

The advent of highly sensitive imaging techniques and trephine biopsy has improved the detection of bone marrow metastases and granulomatosis leading to myelophthisis. However, epidemiological estimates are limited by methodology (mixed causes of anemia in cancer patients), so exact percentages vary between studies and registries. [12]

Table 2. Where to most often look for myelophthisis in adults

Category	Examples	Comment
Solid tumors	Mammary gland, prostate, lung	“Less than 10%” of metastases may have a myelophthisic picture. [13]
Hematological diseases	Primary myelofibrosis, lymphomas	Frequent leukoerythroblastosis and dacryocytes. [14]
Inflammatory/granulomatoses	Tuberculosis, sarcoidosis (less common)	Rarely, but possible with massive infiltration. [15]

Reasons

The mechanism is general: replacement/displacement of hematopoietic tissue. The primary causes are metastases from solid tumors (breast, prostate, lung, stomach, etc.) and lymphoproliferative processes. Infiltration destroys the stromal microenvironment, disrupts stem cell niches, and leads to hypoproliferation of all lineages. [16]

The second set of causes is primary myelofibrosis and other forms of severe bone marrow fibrosis. Bone marrow scarring physically limits the space for hematopoiesis, and the release of inflammatory factors exacerbates cytopenias. Such patients are characterized by massive splenomegaly and extramedullary hematopoiesis. [17]

The third block is granulomatous and infiltrative processes (tuberculosis, sarcoidosis), as well as rare infiltrates (histiocytosis, etc.). In these scenarios, myelophthisis is part of a general systemic pathology and requires etiotropic therapy (anti-tuberculosis, immunomodulatory, etc.). [18]

Risk factors

The main factor is the presence of widespread cancer with possible dissemination to the bone marrow. The risks are higher in hormone-dependent tumors with a bone predilection (breast and prostate cancer) and in long-term disease. In lymphomas and leukemias, concordant bone marrow infiltration worsens the prognosis compared to discordant infiltration. [19]

For myelofibrosis, risk factors for anemia include high inflammatory activity, massive splenomegaly, and fibrosis progression—these are predictors of significant extramedullary hematopoiesis and a myelophthisic blood picture. Additional triggers include iron/folate deficiencies and concomitant kidney disease. [20]

Pathogenesis

Bone marrow infiltration disrupts the architecture of the "niche" and destroys the "blood-marrow" barrier. This causes the premature release of immature cells into the bloodstream (leukoerythroblastosis), the appearance of normoblasts and "tear" erythrocytes (deformed when passing through fibrosis/infiltrate). The result is combined hypoproliferative anemia with low reticulocytosis and often thrombocytopenia/neutropenia. [21]

In parallel, extramedullary hematopoiesis (liver, spleen) is activated as a compensatory mechanism, but it rarely fully compensates for the deficiency. In tumor-related conditions, inflammatory anemia and/or chemotherapy-induced anemia are added, creating a mixed picture. [22]

Symptoms

The main complaints are related to anemia: weakness, fatigue, shortness of breath on exertion, tachycardia, and dizziness. With concomitant thrombocytopenia, bleeding gums, petechiae, and bruising appear; with neutropenia, a tendency to infections and fever. Some patients report bone pain and splenomegaly (especially in myelofibrosis). [23]

Cancer patients often report worsening symptoms as the disease progresses or treatment changes. A sudden increase in weakness and the appearance of an "atypical" smear pattern are reasons to urgently examine the bone marrow for metastases or fibrosis. [24]

Classification, forms and stages

Myelophthisis is classified by the cause: 1) tumor-associated (metastases of solid tumors, lymphomas), 2) fibrosis-associated (primary myelofibrosis, etc.), 3) granulomatous/infectious (tuberculosis, sarcoidosis, etc.). According to severity, compensated (moderate anemia) and decompensated forms (severe anemia with cytopenias and organ dysfunction) are distinguished. [25]

For practice, it is convenient to indicate the “background” of anemia in parallel: concomitant inflammatory anemia, chemo-induced anemia, deficiency anemia - this influences the choice of maintenance therapy (for example, the benefit of erythropoiesis stimulators in cancer patients on active chemotherapy). [26]

Table 3. Etiological groups of myelophthisis

Group	Examples	Diagnostic clues
Tumors	Metastases from breast, prostate, and lung cancer; lymphoma	Leukoerythroblastosis, dacryocytes, hypoproliferative reticulocytosis, “dry puncture” → trephine biopsy. [27]
Fibrosis	Primary myelofibrosis	Splenomegaly, extramedullary hematopoiesis, JAK inhibitors in therapy. [28]
Granulomatosis/infections	Tuberculosis, sarcoidosis	Granulations/granulomas in trephine biopsy, treatment of the cause. [29]

Complications and consequences

In addition to anemia symptoms, bleeding (thrombocytopenia) and infections (neutropenia) are clinically significant. Long-term anemia worsens the survival of cancer patients and the tolerability of antitumor therapy. In myelofibrosis, massive splenomegaly can cause pain, early satiety, and portal complications. [30]

Lack of timely diagnosis leads to delayed detection of bone marrow metastases and loss of the "therapeutic window." In certain scenarios (for example, with pump-dependent transfusions), the risk of iron overload increases, requiring ferritin monitoring and, if necessary, chelation therapy. [31]

When to see a doctor

Urgently - with a sharp increase in weakness, dizziness, shortness of breath with minimal exertion, fever in neutropenic patients, the appearance of significant bruising or bleeding, black stools/blood in the urine. These symptoms require immediate evaluation of a complete blood count, reticulocyte count, biochemistry, and possibly hospitalization. [32]

Planned - in cases of persistent anemia of "unclear genesis," the appearance of leukoerythroblastosis or dacryocytes in a smear, an enlarged spleen, bone pain, especially in patients with a known cancer diagnosis or myeloproliferative disease. In these cases, verification of the cause at the bone marrow level is necessary. [33]

Diagnostics

Step 1: Confirm anemia as hypoproliferative. Complete blood count, reticulocyte count (usually low for the degree of anemia), biochemical markers of hemolysis (usually no evidence of significant hemolysis), iron/ferritin/TFSS, and folate/vitamin B12 to rule out deficiencies. [34]

Step 2. Examine the "signal" smear. Leukoerythroblastosis (normoblasts + immature granulocytes), dacryocytes, and sometimes aniso- and poikilocytosis. This pattern is a strong argument in favor of myelophthisis/myelofibrosis and a basis for proceeding to morphological verification. [35]

Step 3. Bone marrow morphology. The puncture may be "dry" (due to fibrosis), so a trephine biopsy is indicated: it reveals bone marrow replacement (metastases, granulomas) or severe fibrosis. Immunohistochemistry/molecular panels are also used to clarify the type of infiltrate. [36]

Step 4. Search for the cause and prevalence. Imaging (CT/PET-CT/MRI of the skeleton) if metastases are suspected; in myelofibrosis - molecular profile (JAK2, CALR, MPL). In cancer patients - staging examinations and revision of systemic therapy; in granulomatosis - microbiological/immunological verification. [37]

Table 4. Diagnostic route for suspected myelophthisis

Question	What are we doing?	For what
Hypoproliferation?	Complete blood count + reticulocytes, exclude hemolysis/deficiencies	We differentiate types of anemia. [38]
"Signal" smear?	Leukoerythroblastosis, dacryocytes	Direct hint of infiltration/fibrosis. [39]
Morphology?	Trepanobiopsy (if "dry" puncture)	We confirm bone marrow replacement, type of infiltrate. [40]
What is the reason?	Staging/molecular testing	Affects etiotropic therapy. [41]

Differential diagnosis

Anemia of chronic disease/inflammation is normocytic but without leukoerythroblastosis and dacryocytes; reticulocytes are usually moderately reduced, ferritin is high as is acute phase protein. Hemolytic anemias produce high reticulocytosis and markers of hemolysis; the smear contains schistocytes/spherocytes (due to the cause) and is not typical of myelophthisis.[42]

Anemia due to blood loss is accompanied by reticulocytosis after 3-5 days; aplastic anemia (idiopathic) is characterized by empty bone marrow without infiltrates and without leukoerythroblastosis; deficiency anemias (iron, folate, B12) have characteristic erythrocyte indices and erythrocyte morphology (micro/macrocytosis, hyperchromasia, hypersegmentation of neutrophils). [43]

Table 5. How myelophthisis differs from its “neighbors”

State	Reticulocytes	Smear	Bone marrow
Myelophthisis	Low for the degree of anemia	Leukoerythroblastosis, dacryocytes	Infiltration/fibrosis
Anemia of inflammation	Normal/slightly low	Without leukoerythroblastosis	Hypocellular/normal
Hemolysis	Tall	Schistocytes/spherocytes	Erythroid hyperplasia
Aplastic anemia	Low	Without leukoerythroblastosis	Empty/hypocellular

Treatment

Therapy is always twofold: treating the underlying cause of bone marrow replacement while simultaneously providing supportive measures. In cancer patients with verified bone marrow metastases, systemic antitumor therapy (hormone therapy for hormone-dependent tumors, chemotherapy/targeted therapy) and/or local radiation therapy to painful and high-risk lesions are considered. The choice of regimen depends on the tumor biology, overall condition, expected sensitivity, and treatment goals. Tumor control often leads to partial restoration of hematopoiesis. [44]

In patients with primary myelofibrosis, the goals are to reduce splenomegaly, improve symptoms, and correct anemia. JAK/STAT inhibitors are the standard of care: ruxolitinib and fedratinib shrink splenomegaly and symptoms; pacritinib is indicated for severe thrombocytopenia; momelotinib (approved by the FDA in 2023) targets patients with anemia and can reduce transfusion dependence. Combination and non-JAK approaches are being discussed in 2024-2025, but they are still "on the way" or in trials. [45]

Supportive therapy includes restrictive red blood cell transfusions for symptomatic anemia, correction of deficiencies (iron/folate/vitamin B12), prevention and treatment of infections in neutropenia, and hemostatic measures in thrombocytopenia. In cancer patients undergoing active chemotherapy with symptomatic anemia and low levels of endogenous erythropoietin, the use of erythropoiesis-stimulating drugs is permissible according to oncohematological guidelines, taking into account the risks (thrombosis, impact on the tumor). The decision is made on an individual basis. [46]

In cases of severe, painful bone lesions and locally dominant myelophthisis, palliative radiation therapy is considered to control pain and risks (e.g., in the case of a risk of compression), which can further improve hematopoiesis by reducing the mass of the infiltrate. In lymphomas, the choice of systemic therapy is determined by the histotype; with "concordant" bone marrow infiltration, the prognosis is worse – this is taken into account when planning the tumor lines. [47]

In granulomatosis (tuberculosis, sarcoidosis), treatment of the underlying cause is the key to restoring hematopoiesis. Antimicrobial/immunomodulatory therapy under the supervision of specialized specialists usually results in regression of infiltration and improvement of blood counts. During the recovery period, supportive transfusions and prevention of complications are appropriate. [48]

In patients with severe cytopenias, strategic considerations are important: vaccination (inactivated vaccines), infection prophylaxis during prolonged neutropenia, fever education, rapid access to antibiotics, caution with nonsteroidal anti-inflammatory drugs (bleeding), and fall prevention in severe anemia. A multidisciplinary team (hematologist, oncologist, radiation therapist, infectious disease specialist) improves safety. [49]

Hematopoietic stem cell transplantation remains the only potentially curative treatment option for selected high-risk patients with primary myelofibrosis, but is not indicated for purely neoplastic myelophthisis. Selection criteria include biological age, comorbidities, molecular risks, and donor availability; pre-treatment with JAK inhibitor therapy improves tolerability. [50]

Iron loading therapy during multiple transfusions requires ferritin monitoring and, if necessary, chelation therapy. Intravenous iron is preferred if deficiency is confirmed (low transferrin saturation with normal/moderately high ferritin). Correction of deficiencies reduces the need for transfusions. [51]

Symptom control: for splenomegaly – analgesics, nutritional support; in cases of severe splenic hyperfunction, radiation therapy to the spleen or splenectomy are considered in some cases, but the risk of infection after splenectomy is high, and the decision is made very carefully. For cancer patients, early involvement of palliative care improves quality of life. [52]

New and promising approaches to myelofibrosis (non-JAK strategies, combinations) are being actively studied, with the goal of more deeply impacting the pathogenesis of anemia and fibrosis. As of 2025, studies of drugs that affect the microenvironment and erythropoiesis are underway; however, these have not yet become routine and are used in clinical trials. [53]

Table 6. “Who - what”: therapy guidelines

Scenario	First line	What to add
Metastases of solid tumors in the BM	Systemic antitumor therapy ± local radiation	Transfusions, correction of deficiencies, ESA as indicated
Myelofibrosis with anemia	JAK inhibitor (eg, momelotinib for anemia)	Consider pacritinib for thrombocytopenia; transplantation in selected patients
Granulomatosis (TB, sarcoidosis)	Etiotropic therapy	Support (transfusions, nutritional correction)

Prevention

There is no specific primary prevention for myelophthisis, as it is a syndrome and not an independent disease. However, timely staging and treatment of oncologic diseases, monitoring the activity of myeloproliferative diseases, and appropriate management of infections/granulomatosis reduce the risk of massive bone marrow infiltration. Vigilance for leukoerythroblastosis and dacryocytes in a smear is important. [54]

In cancer patients, prevention of worsening anemia includes nutritional support, early treatment of deficiencies, appropriate use of erythropoiesis-stimulating drugs when indicated, and minimization of blood loss (e.g., in patients with thrombocytopenia and anticoagulation). [55]

Forecast

The prognosis is determined by the underlying cause of myelophthisis and its controllability. With effective antitumor or antifibrotic therapy, partial restoration of hematopoiesis and a reduction in the need for transfusions are possible. In progressive metastatic processes, the prognosis is determined by the tumor, and myelophthisis is a marker of an unfavorable course. [56]

In primary myelofibrosis, the introduction of JAK inhibitors and, for some patients, allogeneic transplantation has improved symptom control and outcomes, particularly in patients with severe anemia (momelotinib). Supportive measures remain essential and directly impact quality of life. [57]

FAQ

Is this a separate disease?
No. Myelophthisis is a bone marrow replacement syndrome that occurs with various diseases (tumors, myelofibrosis, granulomatosis). The underlying cause is treated first. [58]

What are the "clues" in the tests that suggest myelophthisis?
Leukoerythroblastosis and "tearful" red blood cells against a background of normocytic anemia and low reticulocytosis. The biopsy may be "dry"—a trephine biopsy is needed. [59]

How is anemia treated in myelophthisis?
Supportive care (transfusions, correction of deficiencies, ESAs as indicated in cancer patients) plus etiotropic therapy: antitumor, JAK inhibitors for myelofibrosis, and treatment of the underlying cause for granulomatosis. [60]

How to code the diagnosis?
ICD-10: D61.82 "Myelophthisis" + the code of the underlying disease. ICD-11: 3A70.1Y "Other specified acquired aplastic anemias" with post-coordination of the cause (e.g., 3A71.0 "Anemia in neoplasm"). Check local regulations. [61]