J Hematol

Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc

Journal website https://jh.elmerpub.com

Review

Volume 14, Number 4, August 2025, pages 174-192

Mast Cell Leukemia: Comprehensive Review of Literature With Current Insights and Updates on Management

Figure 2. A clot section of bone marrow biopsy showing dense infiltration and clustering of atypical mast cells with diffuse and increased CD117 expression.

Figure 3. A clot section of bone marrow biopsy with dense infiltration and clustering of atypical mast cells with diffuse tryptase staining.

Figure 4. A high-power view of an iliac bone biopsy showing an increased number of atypical mast cells (black arrows).

Figure 6. A clot section of the iliac bone biopsy showing an increased number of cells with diffuse tryptase staining.

Figure 7. Computed tomography of lumbar spine with contrast showing the osteolytic lesions and pathological fractures in multiple lumbar vertebrae (black arrows).

Figure 8. Computed tomography of lumbar spine with contrast showing the osteolytic lesion with fracture in the L5 lumbar vertebra (black arrow).

Figure 9. Computed tomography of chest with contrast showing the osteoblastic lesions in multiple ribs (black arrows).

Figure 10. Computed tomography of spine with contrast showing the osteoblastic lesions in the sternum and multiple thoracic and lumbar vertebrae (black arrows).

Figure 11. Computed tomography of abdomen and pelvis with contrast showing osteoblastic lesions in the pelvis (appendicular skeleton) (black arrows).

Figure 12. Computed tomography of abdomen and pelvis with contrast showing hepatosplenomegaly and portal vein dilatation (white arrows).

**Table 1.** Classification of Mastocytosis (WHO/ICC)
Type	Key features	Diagnostic criteria	Subtypes	Prognosis
CM: cutaneous mastocytosis; ICC: International Consensus Classification; KIT: receptor tyrosine kinase type III; MC: mast cell; MCL: mast cell leukemia; MCS: mast cell sarcoma; SM: systemic mastocytosis; SM-AHN: SM with associated hematologic neoplasm; WHO: World Health Organization.
CM	Confined to skin; no systemic organ involvement on biopsy or imaging	Clinical and dermatological findings: flushing, itching, urticaria, anaphylaxis; positive Darier’s sign	Maculopapular CM; urticaria pigmentosa; diffuse CM; cutaneous mastocytoma	Excellent; typically normal life expectancy
SM	Involves bone marrow or extracutaneous organs; may cause systemic symptoms and/or organ dysfunction	Requires 1 major + 1 minor OR ≥ 3 minor criteria: major: dense MC aggregates (> 15%); minor: atypical MCs, KIT mutation, CD25/CD2/CD30 expression, serum tryptase > 20 µg/L	Indolent SM; smoldering SM; aggressive SM; SM-AHN; MCL	Varies: indolent types have a good prognosis; aggressive/MCL subtypes have a poor prognosis
MCS	Rare, localized malignant tumor in soft tissue or visceral organ	Histology: highly atypical mast cells in an aggressive and destructive tumor. Typically KIT-mutated	None (distinct from systemic forms; may progress to MCL)	Very poor; rapid progression, often fatal

Table 1. Classification of Mastocytosis (WHO/ICC)

Type

Key features

Diagnostic criteria

Subtypes

Prognosis

CM: cutaneous mastocytosis; ICC: International Consensus Classification; KIT: receptor tyrosine kinase type III; MC: mast cell; MCL: mast cell leukemia; MCS: mast cell sarcoma; SM: systemic mastocytosis; SM-AHN: SM with associated hematologic neoplasm; WHO: World Health Organization.

Confined to skin; no systemic organ involvement on biopsy or imaging

Clinical and dermatological findings: flushing, itching, urticaria, anaphylaxis; positive Darier’s sign

Maculopapular CM; urticaria pigmentosa; diffuse CM; cutaneous mastocytoma

Excellent; typically normal life expectancy

Involves bone marrow or extracutaneous organs; may cause systemic symptoms and/or organ dysfunction

Requires 1 major + 1 minor OR ≥ 3 minor criteria: major: dense MC aggregates (> 15%); minor: atypical MCs, KIT mutation, CD25/CD2/CD30 expression, serum tryptase > 20 µg/L

Indolent SM; smoldering SM; aggressive SM; SM-AHN; MCL

Varies: indolent types have a good prognosis; aggressive/MCL subtypes have a poor prognosis

MCS

Rare, localized malignant tumor in soft tissue or visceral organ

Histology: highly atypical mast cells in an aggressive and destructive tumor. Typically KIT-mutated

None (distinct from systemic forms; may progress to MCL)

Very poor; rapid progression, often fatal

**Table 2.** Brief Overview of Systemic Mastocytosis Subtypes
Subtype	Clinical features	Histopathology	Prognosis
ASM: aggressive systemic mastocytosis; BM: bone marrow; BMM: bone marrow mastocytosis; CMML: chronic myelomonocytic leukemia; ISM: indolent systemic mastocytosis; MC: mast cell; MCL: mast cell leukemia; MDS: myelodysplastic neoplasm; MPN: myeloproliferative neoplasm; SM-AHN: systemic mastocytosis-associated hematologic neoplasm; SSM: smoldering systemic mastocytosis.
ISM	Skin lesions, flushing, itching, abdominal pain, diarrhea, and anaphylaxis. No B-findings or C-findings.	Multifocal aggregates of mast cells in BM biopsy.	Normal life expectancy
BMM	All findings of ISM without skin lesions.	Serum tryptase < 125 µg/L. No dense MC infiltrates in an extramedullary organ.	Normal life expectancy
SSM	Higher MC burden than ISM. More severe symptoms than ISM with organ involvement but without organ damage.	Increased MC burden in BM.	Intermediate prognosis
SM-AHN	Associated with another hematologic disorder, such as MDS/MPN, or AML. CMML is the most common MDS/MPN. Symptoms of MC activation and cytopenias.	BM involvement with both MCs and an associated hematologic neoplasm.	Variable prognosis
ASM	Organ damage or dysfunction due to MC infiltration (C-findings): hepatomegaly, splenomegaly, lymphadenopathy, skeletal lesions, cytopenias, and malabsorption.	MC infiltration and organ damage in various tissues.	Poor prognosis
MCL	ASM+ rapid progression with > 20% MCs in BM aspirate.	BM infiltrated with > 20% MCs.	Poor prognosis

Table 2. Brief Overview of Systemic Mastocytosis Subtypes

Subtype

Clinical features

Histopathology

Prognosis

ASM: aggressive systemic mastocytosis; BM: bone marrow; BMM: bone marrow mastocytosis; CMML: chronic myelomonocytic leukemia; ISM: indolent systemic mastocytosis; MC: mast cell; MCL: mast cell leukemia; MDS: myelodysplastic neoplasm; MPN: myeloproliferative neoplasm; SM-AHN: systemic mastocytosis-associated hematologic neoplasm; SSM: smoldering systemic mastocytosis.

ISM

Skin lesions, flushing, itching, abdominal pain, diarrhea, and anaphylaxis. No B-findings or C-findings.

Multifocal aggregates of mast cells in BM biopsy.

Normal life expectancy

BMM

All findings of ISM without skin lesions.

Serum tryptase < 125 µg/L. No dense MC infiltrates in an extramedullary organ.

Normal life expectancy

SSM

Higher MC burden than ISM. More severe symptoms than ISM with organ involvement but without organ damage.

Increased MC burden in BM.

Intermediate prognosis

SM-AHN

Associated with another hematologic disorder, such as MDS/MPN, or AML. CMML is the most common MDS/MPN. Symptoms of MC activation and cytopenias.

BM involvement with both MCs and an associated hematologic neoplasm.

Variable prognosis

ASM

Organ damage or dysfunction due to MC infiltration (C-findings): hepatomegaly, splenomegaly, lymphadenopathy, skeletal lesions, cytopenias, and malabsorption.

MC infiltration and organ damage in various tissues.

Poor prognosis

MCL

ASM+ rapid progression with > 20% MCs in BM aspirate.

BM infiltrated with > 20% MCs.

Poor prognosis

**Table 3.** Clinical Features and Organ Dysfunctions in MCL
System/feature	Clinical findings	Notes
CNS: central nervous system; DIC: disseminated intravascular coagulation; GI: gastrointestinal; MCAS: mast cell activation syndrome; MCL: mast cell leukemia.
Skin	Blistering lesions	Common in secondary MCL
GI tract	Abdominal pain, diarrhea, peptic ulcers, GI bleeding, malabsorption	Also part of MCAS symptoms
Musculoskeletal system	Bone pain, osteolytic and osteoblastic lesions, pathological fractures, osteoporosis	Osteoblastic lesions less common; non-vertebral metastases rare
Bone marrow	Pancytopenia (anemia, thrombocytopenia, leukopenia), immunosuppression, infections, sepsis	Due to marrow infiltration by mast cells
CNS	Headache, dizziness, cognitive impairment, neuropsychiatric symptoms	CNS involvement is less frequent but clinically significant.
Liver (hepatomegaly)	Transaminitis, hypoalbuminemia, coagulopathy, DIC, ascites, portal hypertension	Liver dysfunction indicates advanced disease.
Spleen (splenomegaly)	Left upper quadrant pain/fullness, early satiety, hypersplenism with cytopenias	May accompany hepatomegaly
Lymph nodes	Diffuse lymphadenopathy; painful in some cases	Due to mast cell infiltration
Constitutional symptoms	Fever, fatigue, anorexia, malaise, weight loss, night sweats, decreased exercise tolerance	Common in chronic MCL
MCAS (systemic)	Anaphylaxis-like symptoms involving cardiovascular (hypotension, tachycardia, syncope), cutaneous (flushing, urticaria, pruritus), respiratory (wheezing, dyspnea, stridor), and GI (nausea, vomiting, diarrhea, abdominal pain)	It can occur at any stage/type of MCL. The best marker is elevated serum tryptase level.

Table 3. Clinical Features and Organ Dysfunctions in MCL

System/feature

Clinical findings

Notes

CNS: central nervous system; DIC: disseminated intravascular coagulation; GI: gastrointestinal; MCAS: mast cell activation syndrome; MCL: mast cell leukemia.

Skin

Blistering lesions

Common in secondary MCL

GI tract

Abdominal pain, diarrhea, peptic ulcers, GI bleeding, malabsorption

Also part of MCAS symptoms

Musculoskeletal system

Bone pain, osteolytic and osteoblastic lesions, pathological fractures, osteoporosis

Osteoblastic lesions less common; non-vertebral metastases rare

Bone marrow

Pancytopenia (anemia, thrombocytopenia, leukopenia), immunosuppression, infections, sepsis

Due to marrow infiltration by mast cells

CNS

Headache, dizziness, cognitive impairment, neuropsychiatric symptoms

CNS involvement is less frequent but clinically significant.

Liver (hepatomegaly)

Transaminitis, hypoalbuminemia, coagulopathy, DIC, ascites, portal hypertension

Liver dysfunction indicates advanced disease.

Spleen (splenomegaly)

Left upper quadrant pain/fullness, early satiety, hypersplenism with cytopenias

May accompany hepatomegaly

Lymph nodes

Diffuse lymphadenopathy; painful in some cases

Due to mast cell infiltration

Constitutional symptoms

Fever, fatigue, anorexia, malaise, weight loss, night sweats, decreased exercise tolerance

Common in chronic MCL

MCAS (systemic)

Anaphylaxis-like symptoms involving cardiovascular (hypotension, tachycardia, syncope), cutaneous (flushing, urticaria, pruritus), respiratory (wheezing, dyspnea, stridor), and GI (nausea, vomiting, diarrhea, abdominal pain)

It can occur at any stage/type of MCL. The best marker is elevated serum tryptase level.

**Table 4.** Summary of Common Drugs Used to Manage MCL and Their Notable Adverse Effects
Treatment category/drug	Role in management	Adverse/side effects
AdvSM: advanced systemic mastocytosis; AHN: associated hematological neoplasm; AIHA: autoimmune hemolytic anemia; ARDS: acute respiratory distress syndrome; CHF: congestive heart failure; FDA: Food and Drug Administration; GI: gastrointestinal; HSCT: hematopoietic stem cell transplantation; IFN-α: interferon-alpha; ILD: interstitial lung disease; ITP: immune thrombocytopenic purpura; MC: mast cell; MCAS: mast cell activation syndrome; MCL: mast cell leukemia; PUD: peptic ulcer disease; SM: systemic mastocytosis.
Targeted therapy: tyrosine kinase inhibitors Mainstay of treatment currently. Midostaurin and avapritinib are the two agents approved by the FDA for MCL.	Midostaurin	Improved prognosis in all types of MCL irrespective of the stage of the disease.	Hyperglycemia; GI symptoms; myelosuppression (manageable); rare: arrhythmias, pneumonitis, hepatotoxicity
	Avapritinib (only used if platelets are > 50,000)	Good response rate even in the most aggressive forms of MCL. Favorable risk profile with fewer adverse effects when compared.	Pancytopenia; risk of intracranial bleeding (rare); peripheral and periorbital edema; GI issues; cognitive impairment
	Imatinib	Mainly effective in patients without the KIT D816V mutation, some patients even achieving complete response. In patients with D816V mutation, only a partial response is noted.	Pancytopenia; fatigue, myalgias; GI symptoms; rare but serious: CHF, arrhythmias, hepatotoxicity, severe myelosuppression
	Dasatinib	Only theoretical benefit noted in KIT D816V positive cases. Even in D816V negative cases, response rates and adverse effects were undesirable.	All the above adverse effects of imatinib +; rare: pulmonary arterial hypertension, pancreatitis, pleural effusion
	Bezuclastinib	Drug in clinical trials with promising improvement in the disease markers and no serious adverse effects.	Pancytopenia; GI issues and taste disorders; rare and serious: hepatotoxicity, hypersensitivity reaction
Chemotherapy: Out of favor with the invention of targeted therapy. Tumor debulking to decrease MC burden and related symptoms. Pre- and post-HSCT to prolong remission and improve survival. Main treatment for aggressive AHN.	Cladribine	Potential value in other forms of AdvSM, but very little, and transient response seen in MCL. Used as a monotherapy or as a part of multidrug therapy for tumor debulking and before HSCT.	Adverse effects that are common to all chemo drugs: rash and pruritic; flu-like symptoms; GI symptoms; bone marrow suppression with increased risk of infections; hepatotoxicity (transaminitis); fatigue and malaise; tumor lysis syndrome	Arrhythmias; increased risk of AHN
	Cytarabine	Used in combination with cladribine for tumor debulking and with fludarabine before HSCT.		Cerebellar toxicity; peripheral neuropathy; rare: cytarabine syndrome, ARDS, pancreatitis
	Fludarabine	Used as a part of polychemotherapy with either cladribine or cytarabine, mainly before HSCT.		Encephalopathy/coma and seizures; AIHA and ITP; heart failure; ILD and pulmonary fibrosis
	IFN-α	Limited role in MCL. Studied in combination with steroids.		Psychiatric issues; thyroid dysfunction, alopecia; peripheral neuropathy; ILD and pulmonary fibrosis (rare)
Immuno-modulators: No disease-modifying effect. Used to manage MC-related symptoms alongside chemotherapy or targeted therapies. Commonly employed in the treatment of MCAS.	Thalidomide	Can be used as a single therapy for benign forms of SM. Not well studied in AdvSM/MCL; can be used to control MC symptoms.	Drowsiness and sedation; peripheral neuropathy; pancytopenia
	Cromolyn	Control symptoms and improve quality of life in all forms of SM. Important role in MCAS.	Rash and pruritus; dizziness; GI symptoms (nausea, vomiting, diarrhea); paradoxical bronchospasm; fatigue and malaise
	Cortico-steroids	Main role in refractory and severe (anaphylaxis) cases of MCAS. Control of musculoskeletal pain associated with bone metastases. Used in organ damage from MC infiltration, particularly GI issues.	Typically, not used long enough to cause adverse effects: muscle weakness; Cushingoid features; PUD and GI bleeding; increased risk of infections; vision changes, headache, and psychosis

Table 4. Summary of Common Drugs Used to Manage MCL and Their Notable Adverse Effects

Treatment category/drug

Role in management

Adverse/side effects

AdvSM: advanced systemic mastocytosis; AHN: associated hematological neoplasm; AIHA: autoimmune hemolytic anemia; ARDS: acute respiratory distress syndrome; CHF: congestive heart failure; FDA: Food and Drug Administration; GI: gastrointestinal; HSCT: hematopoietic stem cell transplantation; IFN-α: interferon-alpha; ILD: interstitial lung disease; ITP: immune thrombocytopenic purpura; MC: mast cell; MCAS: mast cell activation syndrome; MCL: mast cell leukemia; PUD: peptic ulcer disease; SM: systemic mastocytosis.

Targeted therapy: tyrosine kinase inhibitors
Mainstay of treatment currently.
Midostaurin and avapritinib are the two agents approved by the FDA for MCL.

Midostaurin

Improved prognosis in all types of MCL irrespective of the stage of the disease.

Hyperglycemia; GI symptoms; myelosuppression (manageable); rare: arrhythmias, pneumonitis, hepatotoxicity

Avapritinib (only used if platelets are > 50,000)

Good response rate even in the most aggressive forms of MCL. Favorable risk profile with fewer adverse effects when compared.

Pancytopenia; risk of intracranial bleeding (rare); peripheral and periorbital edema; GI issues; cognitive impairment

Imatinib

Mainly effective in patients without the KIT D816V mutation, some patients even achieving complete response. In patients with D816V mutation, only a partial response is noted.

Pancytopenia; fatigue, myalgias; GI symptoms; rare but serious: CHF, arrhythmias, hepatotoxicity, severe myelosuppression

Dasatinib

Only theoretical benefit noted in KIT D816V positive cases.
Even in D816V negative cases, response rates and adverse effects were undesirable.

All the above adverse effects of imatinib +; rare: pulmonary arterial hypertension, pancreatitis, pleural effusion

Bezuclastinib

Drug in clinical trials with promising improvement in the disease markers and no serious adverse effects.

Pancytopenia; GI issues and taste disorders; rare and serious: hepatotoxicity, hypersensitivity reaction

Chemotherapy:
Out of favor with the invention of targeted therapy.
Tumor debulking to decrease MC burden and related symptoms.
Pre- and post-HSCT to prolong remission and improve survival.
Main treatment for aggressive AHN.

Cladribine

Potential value in other forms of AdvSM, but very little, and transient response seen in MCL. Used as a monotherapy or as a part of multidrug therapy for tumor debulking and before HSCT.

Adverse effects that are common to all chemo drugs: rash and pruritic; flu-like symptoms; GI symptoms; bone marrow suppression with increased risk of infections; hepatotoxicity (transaminitis); fatigue and malaise; tumor lysis syndrome

Arrhythmias; increased risk of AHN

Cytarabine

Used in combination with cladribine for tumor debulking and with fludarabine before HSCT.

Cerebellar toxicity; peripheral neuropathy; rare: cytarabine syndrome, ARDS, pancreatitis

Fludarabine

Used as a part of polychemotherapy with either cladribine or cytarabine, mainly before HSCT.

Encephalopathy/coma and seizures; AIHA and ITP; heart failure; ILD and pulmonary fibrosis

IFN-α

Limited role in MCL. Studied in combination with steroids.

Psychiatric issues; thyroid dysfunction, alopecia; peripheral neuropathy; ILD and pulmonary fibrosis (rare)

Immuno-modulators:
No disease-modifying effect.
Used to manage MC-related symptoms alongside chemotherapy or targeted therapies.
Commonly employed in the treatment of MCAS.

Thalidomide

Can be used as a single therapy for benign forms of SM. Not well studied in AdvSM/MCL; can be used to control MC symptoms.

Drowsiness and sedation; peripheral neuropathy; pancytopenia

Cromolyn

Control symptoms and improve quality of life in all forms of SM. Important role in MCAS.

Rash and pruritus; dizziness; GI symptoms (nausea, vomiting, diarrhea); paradoxical bronchospasm; fatigue and malaise

Cortico-steroids

Main role in refractory and severe (anaphylaxis) cases of MCAS. Control of musculoskeletal pain associated with bone metastases. Used in organ damage from MC infiltration, particularly GI issues.

Typically, not used long enough to cause adverse effects: muscle weakness; Cushingoid features; PUD and GI bleeding; increased risk of infections; vision changes, headache, and psychosis