Myeloid sarcoma also known as chloroma (owing to its green color attributed to the enzyme myeloperoxidase [MPO]), granulocytic sarcoma, myeloblastoma, extramedullary myeloid cell tumor or extramedullary leukemia 1. Myeloid sarcoma is a subgroup of acute myeloid leukemia (AML) where myeloid blasts (immature blood cells) form a tumor mass in extramedullary tissues that disrupt the normal architecture of the tissue in which it is found 2. Myeloid sarcoma develops most often in the bone, skin, lymph nodes, breast, ovary, meninges (membranes that cover and protect the brain or the spinal cord) and around the eye. Therefore, myeloid sarcoma diagnosis is equivalent to a diagnosis of AML 3. The 2008 World Health Organization (WHO) classification clarified the diagnosis of myeloid sarcoma as follows: “a tumor mass consisting of myeloid blasts with or without maturation occurring at an anatomic site other than the bone marrow (BM)” 4. Myeloid sarcoma may occur at any point during acute myeloid leukemia (AML) disease course and almost every site of the body can be affected 3.
Myeloid sarcoma has been described in 2.5–9.11% of patients with acute myeloid leukemia (AML) during the disease course 5. According to the 2016 WHO classification, myeloid sarcoma may include the clinical presentation of any subtype of AML, present de novo (de novo myeloid sarcoma), be accompanied by peripheral blood and bone marrow involvement (myeloid sarcoma with peripheral blood or bone marrow involvement), present as relapse of AML (relapse of AML), or present as the progression of a prior myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), or both (progression of myelodysplastic syndrome or myeloproliferative neoplasms) 2. In most cases, patients with myeloid sarcoma have a history of preexisting AML, myelodysplastic syndrome or myeloproliferative neoplasms 6. However, primary myeloid sarcoma may occur de novo, concurrently with or preceding the diagnosis of AML, and it constitutes 27% of all myeloid sarcoma diagnoses 7. Isolated myeloid sarcoma may present without any preexisting condition and a lack of bone marrow involvement 6; however, virtually all of these patients will develop overt hematologic disease if left untreated 8, which further highlights the systemic nature of this disease. Beside isolated myeloid sarcoma, extramedullary manifestations might also occur simultaneously with leukemic bone marrow infiltration.
The diagnosis of myeloid sarcoma in patients with an established acute myeloid leukemia (AML) is relatively straightforward and should always be included in the differential diagnosis of patients with AML who develop a soft tissue mass. In clinical practice in these patients it is to always attempt to obtain a tissue sample to confirm the diagnosis if the risks of biopsy are reasonable 9. In general, a fine needle aspiration is usually not adequate for diagnosing a hematologic malignancy; however, when obtained, immunohistochemistry of the leukemia cells can be valuable. The morphologic appearance of myeloid sarcoma on hematoxylin and eosin stain can vary according to the degree of myeloid differentiation. Myeloid sarcoma typically consists of a diffuse and infiltrative population of myeloblasts and granulocytic cell components (Figure 2). The malignant cells are typically large with abundant cytoplasm and large nuclei. Importantly, the neoplastic cell lineage should be consistent with the underlying leukemia. In addition, send the tissue samples for immunohistochemistry and, when feasible, for flow cytometry, fluorescence in situ hybridization, and molecular analysis, although these assays are more difficult to perform on cells in tissue than bone marrow.
Immunohistochemistry is the most practical method for establishing the diagnosis of myeloid sarcoma and can be an easier than flow cytometry, which requires cells to be in suspension. Myelocytic differentiation can be confirmed by Leder stain 10, which historically has been helpful in establishing the diagnosis in the absence of bone marrow leukemia. Immunohistochemistry can also discriminate between myeloid and nonmyeloid cells with monoclonal antibodies to myeloperoxidase (MPO) and lysozyme helpful in this regard 11. Myeloperoxidase staining is very often positive in the malignant cells of extramedullary acute leukemia, which is a quick way for establishing the diagnosis and ruling out other tumors. A panel of immunohistochemical markers can be added for diagnosis confirmation and further lineage characterization 12. CD68-KP1 is the most commonly expressed marker followed by myeloperoxidase 13.
In the absence of a clinical history of leukemia, a diagnosis of myeloid sarcoma can be difficult, so always make every effort to obtain a tissue diagnosis. Myeloid sarcoma can often be misdiagnosed, most typically as non-Hodgkin lymphoma, in up to 46% of patients 14. This occurs most often with poorly differentiated myeloid sarcoma, in which the morphology may resemble large-cell non-Hodgkin lymphoma when the cells are MPO-negative and weakly stained 15. Included in the differential diagnosis of myeloid sarcoma are other forms of non-Hodgkin lymphoma, lymphoblastic leukemia, melanoma, Ewing sarcoma, blastic plasmacytoid dendritic cell neoplasm, and extramedullary hematopoiesis 16. Similar to patients with a history of leukemia, send the tissue samples for immunohistochemistry, flow cytometry, fluorescence in situ hybridization, and molecular analysis. In addition, once the extramedullary mass is established as leukemia, perform a bone marrow biopsy, which is sent for identical studies.
Given the wide variety of sites in which myeloid sarcoma develops, imaging can facilitate diagnosis and monitor treatment response. Myeloid sarcoma often appears as a soft-tissue mass best suited to imaging by computed tomography 17. Positron emission tomography (PET) can also be used and is particularly helpful for radiation therapy (radiation therapy) planning and monitoring response to treatment. When myeloid sarcoma develops in the CNS, magnetic resonance imaging is useful 18. Myeloid sarcoma uniformly enhances with gadolinium, which should be administered when there are no contraindications 17. The radiographic appearance of myeloid sarcoma was recently reviewed by Fritz et al 19 with many representative images provided. In clinical practice, computed tomography is routinely performed with consideration of a combined positron emission tomography scan if radiation therapy is planned.
Given the scarcity of positively diagnosed myeloid sarcoma and randomized prospective trials, there is at present no consensus myeloid sarcoma specific therapeutic regimen. The current routine includes conventional AML-type chemotherapy and radiotherapy for both isolated and myeloid sarcoma or myeloid sarcoma with concomitant AML. Studies led by different groups have shown that standard AML therapy exhibits better overall survival in case of isolated myeloid sarcoma incidents 20. Nevertheless, there is a lack of data addressing a particular chemotherapeutic regimen for myeloid sarcoma. Existing data indicates cytarabine to be an essential drug in this regard 21.
The use of radiotherapy is also not well studied as a prospective means of treatment of myeloid sarcoma. Although, in some instances, radiation is used in combination with chemotherapy to treat myeloid sarcoma. However, no added advantage was observed in those cases 22. In addition, hematopoietic stem cell transplantation is also used, albeit retrospectively, in myeloid sarcoma patients 23. Reported data does suggest an advantage of auto- or allogenic-hematopoietic cell transplantation in myeloid sarcoma patients with or without concomitant AML irrespective of age, gender, anatomic location, clinical presentation or cytogenic status 24. In addition, retrospective chemotherapy trials conducted by the Children’s Cancer Group demonstrated a better event-free survival for children with isolated myeloid sarcoma than patients with concurrent AML 25.
Taken together, however, no studies ever compared the different prognostic factors in myeloid sarcoma patients with or without AML and consequently, their effects on the treatment regimens. The published data, nevertheless, do suggest a difference in prognosis between patients with isolated myeloid sarcoma and with concurrent or relapsed AML. Traditionally, the simultaneous expression of myeloid sarcoma at diagnosis of AML is considered as poor prognosis. However, there is evidence contrary to this observation.
As stated above, till now there is no specific treatment for myeloid sarcoma. Consequently, to a large extent the treatment of myeloid sarcoma depends on the site, volume as well as the timing of diagnosis of the extramedullary tumor. Based on these factors, the clinicians determine the treatment plan by employing singly chemotherapy, radiation therapy or bone marrow transplantation or in combination. A detailed discussion of these different therapeutic regimens is discussed below.
Figure 1. Extramedullary myeloid sarcoma
Footnotes: (A) A 17-year-old boy presented with a 1-week history of proptosis of the left eye. Physical examination revealed a tumor involving the periorbital region. (B) Magnetic resonance imaging revealed an orbital mass. Laboratory test results included a hemoglobin level of 89 g per liter, a platelet count of 90,000 per cubic millimeter, and a leukocyte count of 1100 per cubic millimeter. (C, arrow) Morphologic examination of a bone marrow aspirate revealed 30% myeloblasts. There were no circulating myeloblasts. A biopsy specimen of the orbital mass showed myeloid sarcoma. (D) After the patient underwent induction chemotherapy, the mass disappeared and the eye returned to its normal position. He subsequently underwent cord-blood transplantation, and at the 6-year follow-up, there was no evidence of recurrence of AML.[Source 26 ]
Figure 2. Myeloid sarcoma histology
Footnote: Histologic appearance of myeloid sarcoma. (A) Hematoxylin and eosin staining of a myeloid sarcoma along the right psoas muscle (original magnification ×40), demonstrating blasts in the skeletal muscle. Dense dermal infiltrate of monocytic leukemic cells (B; original magnification ×10; C: original magnification ×40), consistent with leukemia cutis.[Source 9 ]
What are the salvage treatment options for bone marrow and extramedullary leukemia relapse?
Frequently, myeloid sarcoma develops concurrently with marrow relapse. Reinduction chemotherapy is always warranted. Consider radiation therapy in patients in whom a complete response is not achieved with chemotherapy. The potential benefits of hematopoietic cell transplantation in this setting are not defined and should be carefully considered. When bone marrow and extramedullary leukemia relapse occurs synchronously after transplantation, survival is very poor 27 and so consider entry into a clinical trial or palliative measures depending on the context.
When is the addition of radiation therapy indicated?
There have been limited studies addressing the role of radiation therapy in the management of myeloid sarcoma 28. In clinical practice, consider radiation therapy in patients with isolated myeloid sarcoma, inadequate response to chemotherapy, recurrence after hematopoietic cell transplantation, and in circumstances that require rapid symptom relief because of vital structure compression. Radiation therapy results in excellent, durable local control at the targeted site 29; however, it is not clear that the addition of radiation therapy results in a superior overall outcome compared with chemotherapy alone. A low-dose radiation therapy regimen of 24 Gy in 12 fractions using conventional treatment can be applied to the majority of patients with excellent disease control and minimal morbidity 29. Notably, radiation therapy within these dose ranges does not preclude using total body irradiation as an hematopoietic cell transplantation conditioning regimen or vice versa.
Should patients with acute promyelocytic leukemia undergo CNS prophylaxis for extramedullary leukemia disease?
The increasingly reported number of acute promyelocytic leukemia patients with CNS relapse is of concern because of its poor associated outcome in an otherwise favorable disease. The Gruppo Italiano Malattie Ematologiche dell’Adulto recently reported that the proportion of CNS relapses among all relapses has increased in the more recent AIDA (all-trans retinoic acid + idarubicin) 2000 study compared with there earlier protocol AIDA 0493 study conducted during the 1990s 30. It is not clear whether the administration of all-trans-retinoic acid contributes to the possible increased incidence in the all-trans–retinoic acid era or whether it is attributable to prolonged overall survival. CNS disease appears to occur in patients with high-risk disease; therefore, it is reasonable for those patients to receive intrathecal prophylaxis to prevent extramedullary leukemia (CNS) disease once in remission. Although further study is needed to determine how to prevent CNS relapses, experts consider prophylactic intrathecal therapy for patients with relapsed acute promyelocytic leukemia who present with or develop leukocytosis during the initial phase of treatment. The best prophylaxis approach has not been determined, but experts usually administer 5 doses of intrathecal methotrexate during the consolidation cycles without cranial radiation.
Myeloid sarcoma causes
The precise mechanism underlying the development of myeloid sarcoma is unclear. However, extramedullary infiltration by acute leukemia strongly implicates the presence of an alternative homing signal that enables the blast cells to re-localize to these secondary sites. In this context, strong evidence was provided by the studies demonstrating the presence of different chemokine receptors on blast cells in myeloid sarcoma and concurrent AML involving blood and bone marrow 31. Taken together, these observations led to the proposal that unusual manifestations of adhesion molecules dictate the migration of AML subclones to surrounding tissues. Stefanidakis et al. 32 provided further insights into the migratory capacity of blast cells. In their study, the authors reported that a major factor for the migration of AML cells into non-myeloid regions is the interactions between matrix metalloproteinase (MMP) – 9 and leukocyte β2 integrin along with some unidentified proteins 32. Stefanidakis et al. termed the complex, ‘invadosome’ 32. The observations that highly invasive AML cell lines express high level of MMP-2 and tissue inhibitor of metalloproteinase 2 (TIMP2) further support the conclusion of Stefanidakis and colleagues 33. In a recent study, Zhu et al. 34 has reported a correlation between high expression of enhancer of Zeste 2 (EZH2), the catalytic subunit of polycomb repressor complex 2 (PRC2), and extramedullary infiltration of AML. The authors have indicated that increased expression of EZH2 attenuates the expression of TIMPs, which result in the upregulation of MMPs. The uninhibited MMPs ultimately degrades the extracellular matrix (ECM) and thus aid in the escape of the blast cells in the extramedullary space 34.
Myeloid sarcoma signs and symptoms
Myeloid sarcoma is a tumor composed of myeloid blasts that occurs at an extramedullary site. However, there is a lack of study to establish a correlation between acute myeloid leukemia (AML) and predilection for sites by myeloid sarcoma. The most commonly involved sites of myeloid sarcoma are skin, bone and lymph nodes 20. In addition, other sites associated with myeloid sarcoma include central nervous system (CNS), oral and nasal mucosa, breasts, genitourinary tract, chest wall, testis etc. Skin is the primary sites for the development of myeloid sarcoma in pediatric patients (∼54%), followed by ocular region 35.
In majority of instances, myeloid sarcoma is asymptomatic. Even so, depending on the size and location of the tumor, the most common signs and symptoms associated with myeloid sarcoma are compression accompanied by pains, bleeding, fever and fatigues 23.
Myeloid sarcoma may occur on its own or concurrently with a myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN) or acute myeloid leukemia (AML); on rare occasions, myeloid sarcoma precedes a diagnosis of AML by months or years 9. According to the 2016 WHO classification, myeloid sarcoma may include the clinical presentation of any subtype of AML, present de novo (de novo myeloid sarcoma), be accompanied by peripheral blood and bone marrow involvement (myeloid sarcoma with peripheral blood or bone marrow involvement), present as relapse of AML (relapse of AML), or present as the progression of a prior myelodysplastic syndrome, myeloproliferative neoplasm or both (progression of myelodysplastic syndrome or myeloproliferative neoplasms) 2. In most cases, patients with myeloid sarcoma have a history of preexisting AML, myelodysplastic syndrome or myeloproliferative neoplasms 6. However, primary myeloid sarcoma may occur de novo, concurrently with or preceding the diagnosis of AML, and it constitutes 27% of all myeloid sarcoma diagnoses 7. Isolated myeloid sarcoma may present without any preexisting condition and a lack of bone marrow involvement 6; however, virtually all of these patients will develop overt hematologic disease if left untreated 8, which further highlights the systemic nature of this disease. Beside isolated myeloid sarcoma, extramedullary manifestations might also occur simultaneously with leukemic bone marrow infiltration. The frequency with which certain myeloid sarcoma sites are accompanied by bone marrow involvement has not been adequately studied. The clinical manifestations of myeloid sarcoma are diverse given the various sites of occurrence, with signs and symptoms determined by its specific location and size. The most common locations include the soft tissue, bone, periosteum, and lymph nodes; however, numerous sites have been described 36. Central nervous system (CNS) involvement is rare 37 and is a distinct entity from meningeal leukemia.
Myeloid sarcoma diagnosis
At present, there is no specific diagnosis for myeloid sarcoma. Given the fact that myeloid sarcoma in majority of cases is asymptomatic and does not elicit any specific symptoms, it often poses serious diagnostic challenge for a clinician. Consequently, myeloid sarcoma is often misdiagnosed as large cell lymphoma, malignant melanoma, extramedullary hematopoiesis or inflammation. However, diagnosis of myeloid sarcoma in association with existing leukemia is comparatively easier than isolated myeloid sarcoma. Detection and identification of myeloid sarcoma requires the coordinated intervention of different medical procedure. Computed tomography (CT) and magnetic resonance imagery (MRI) are generally used for the detection of the tumors 38. Following the detection of tumors biopsies are conducted to confirm the malignancy of the mass.
However, accurate diagnosis of myeloid sarcoma requires histological examination and immunophenotypic analysis. Histological analysis of myeloid sarcoma generally elicits myeloid cells at different stages of maturation. The infiltrating leukemic cells generally elicit irregular large nuclei and large cytoplasm-to-nuclear ratio. Depending on the predominant cell types in the tumors, myeloid sarcoma are classified into granulocytic, monoblastic and myelomonocytic. In addition, depending on the maturity of the cells, myeloid sarcoma are further subdivided into immature, mature and blastic types . In addition to morphology, cytochemical stainings on imprints may allow for confirming the myeloid affiliation and differentiating granulocytic-lineage and monoblastic forms. According to the WHO 2016 classification, cytochemical stains may include myeloperoxidase and naphthol AS-D chloroacetate esterase (positive in granulocytic myeloid sarcoma), as well as non-specific esterase (positive in monoblastic myeloid sarcoma) 39. The diagnosis is further validated by immunophenotyping. Flow cytometric analysis on cell suspensions can be performed; however, immunohistochemistry on paraffin-embedded tissue sections is more commonly used for the detection of lineage affiliation and evaluation of maturation. Myeloid sarcoma are usually positive for myeloid and monocytic markers, i.e. CD33, CD68, lysozyme, the more immature markers such as CD117 and CD34, CD61, glycophorin, CD4, etc. CD99 and TdT may also be positive. CD56 can be detected in around 20% of myeloid sarcoma cases 23. NPM1 cytoplasmic and nuclear staining indicates NPM1 gene mutations. To exclude the possibility of lymphoma the tumors should be interrogated for different T and B lineage markers such as, CD3, CD20, and CD79a. Aberrant expression of B/T-cell markers is possible, however, if criteria for a mixed-lineage leukemia are fulfilled the case is not classified as myeloid sarcoma according to WHO 2016. Particular antigenic constellations may more precisely define subtypes shown in Table 1.
Myeloid sarcoma is also associated with several cytogenetic and chromosomal abnormalities. Consequently, fluorescence in situ hybridization (FISH) should be employed as a part diagnostic work up for patient stratification 40.
Table 1. Common myeloid sarcoma immunophenotypes
Cytogenetics and molecular genetics of myeloid sarcoma
Cytogenetic analysis conducted with bone marrow and peripheral blood blasts in myeloid sarcoma patients has demonstrated cytogenetic abnormalities in more than 50% of instances 41. Nonetheless, the rates of specific cytogenetic abnormalities associated with myeloid sarcoma are rather diverse. Studies have elicited the frequent association of between myeloid sarcoma and core binding factor (CBF) leukemia and AML with MLL rearrangements 42. The most common chromosomal abnormality, t(8;21), is associated with pediatric myeloid sarcoma or in patients with ocular involvement 43. The second predominant chromosomal aberration associated with pediatric myeloid sarcoma is inv16 44. However, studies by Pileri et al. 41 showed the relative rarity of t(8,21) in adult myeloid sarcoma patients. Instead, trisomy 8, monosomy 7 and MLL rearrangements constitute the majority of the cases. The prevalence of inv16 was also not well documented in adult patients. In addition, other chromosomal aberrations including monosomy 5, 7 or 8 were reported in isolated cases. Nucleophosmin (NPM)-1 mutations have been reported to be in 15% of myeloid sarcoma patients. This particular variant of myeloid sarcoma elicits clinical attributes similar to NPM-1 positive AML and manifest primarily in M4 and M5 French American British (FAB) subclasses of AML 45. NPM-1 mutant positive myeloid sarcoma is also associated with the loss of CD34 expression and normal karyotype. Studies conducted by Ansari-Lari et al. have reported the presence of FLT3-ITD mutation in ∼33% (three of nine) of myeloid sarcoma patients with concurrent AML 46. However, the implications of NPM-1 and FLT3-ITD mutations on prognosis of myeloid sarcoma are still not clear and data are too scarce for definite conclusions. In their retrospective study, Vega-Ruiz et al. showed that 3% of patients with acute promyelocytic leukemia (APL) manifest myeloid sarcoma, predominantly in CNS 47. Studies conducted by several groups have also attributed the development of myeloid sarcoma to the use of all-trans retinoic acid (ATRA) or with conventional chemotherapy 48.
Timely identification of myeloid sarcoma has a significant impact on the treatment outcomes and achieving remission in case of AML. As often, these extramedullary tumors serve as sanctuary sites for future relapse. However, detection and simultaneous identification of myeloid sarcoma is challenging. The standard AML diagnosis does not include myeloid sarcoma, nor there are any specific diagnostic regimens for myeloid sarcoma. Consequently, in majority of cases diagnosis of myeloid sarcoma is either significantly delayed or remain undetected. In this context, multimodal imaging procedure can be beneficial for early detection of tumors 49. This generally involves employment of traditional imaging techniques such as, positron emission tomography (PET), CT and MRI 44. Particularly, in the last decades, PET/CT is becoming an essential tool for disease detection 44. In this context, 18F-fluorodeoxygenase (18F-FDG)PET/CT has been recognized as a very potent instrument for the identification of not only leukemia but also extramedullary invasion of blast cells 50. In a prospective study, Stölzel et al. 51 have successfully employed whole-body 18F-FDG PET/CT in 94 AML patients, consisting of both newly diagnosed and relapsed cases of AML for detection of myeloid sarcoma. In a different study, Aschoff et al. 52 have demonstrated the sensitivity of 18F-FDG PET/CT by reducing the number of false-positive associated with traditional PET imaging. In addition, 18F-FDG PET/CT has also been able identify new sites of myeloid sarcoma, which is not identified by traditional imaging techniques 50.
Although, encouraging, 18F-FDG PET/CT does have some restrictions. Several reports have shown that 18F-FDG PET/CT is not sensitive enough to pick up extramedullary infiltration in the soft tissues such as skin meninges and mucus membranes. In addition, 18F-FDG is not a tumor specific marker but rather depends on the glucose uptake by the cells 50. As such, there is an increase chance of false-positive signals associated with 18F-FDG PET/CT specifically, in brain and kidney that have high basal glucose metabolism 53. As an alternative, various groups have used 18F-fluorodeoxythymidine (FLT), a thymidine analogue and proliferating marker, as a tracer for PET/CT in place of 18F-FDG 50. Unlike 18F-FDG, 18F-FLT has generally low uptake in different organs, such as brain and kidney and therefore elicits comparatively less background 54. Although, as of now there has been no prospective/retrospective study with 18F-FLT PET/CT for myeloid sarcoma detection, but the sensitivity and accuracy of 18F-FLT PET/CT has been demonstrated in different cancers including, non-small cell lung cancer (NSCLC) and NPM-ALK-Positive lymphoma 55.
Myeloid sarcoma treatment
Treatment for myeloid sarcoma is dependent on the status of the acute myeloid leukemia (AML), such as whether myeloid sarcoma presents at the time of AML diagnosis, as relapsed AML or as isolated myeloid sarcoma 9. Leukemia cutis almost always represents a local manifestation of underlying systemic disease and therefore should be managed as such. In cases of isolated myeloid sarcoma with no bone marrow involvement, delayed or inadequate treatment will progress to acute myeloid leukemia in about 75% of cases 56.
Although the optimal timing and treatment of isolated myeloid sarcoma are not clear, delayed or inadequately systemically treated isolated myeloid sarcoma will almost always progress to AML 56. The median time to the development of AML in this setting ranges from 5-12 months 57. Using reverse transcription-polymerase chain reaction (RT-PCR), gene fusions specific for AML in the bone marrow of patients with isolated myeloid sarcoma have been detected, suggesting that marrow involvement might occur early in the process before clinical detection 58.
In clinical practice, remission-induction chemotherapy similar to that used for AML is used for treating myeloid sarcoma 9. The postremission chemotherapy has not been adequately studied in isolated myeloid sarcoma; and in particular, the role of hematopoietic cell transplantation is not clear. Experts judge each patient individually and assess multiple prognostic factors, including age, comorbidities, degree of dissemination, and cytogenetic and molecular abnormalities when deciding on a postremission strategy. After chemotherapy, consider radiation therapy as a consolidation treatment for isolated myeloid sarcoma, particularly because the effective radiation therapy dose is low. The radiation site and associated toxicities are important factors in this consideration. In circumstances that require debulking or rapid symptom relief because of compression of a vital structure, consider radiation therapy or even surgery in certain patients upfront, followed by aggressive chemotherapy; however, there is no evidence that this combined approach is superior to aggressive chemotherapy alone 9.
Myeloid sarcoma presenting concurrently with marrow involvement always warrants systemic treatment directed at the underlying leukemia 9. There have been no randomized trials addressing the optimal treatment for patients with extramedullary leukemia involvement. Two retrospective studies have demonstrated superior outcomes with the use of allogeneic or autologous hematopoietic cell transplantation 59. In a study by Chevallier et al 59, which assessed the outcome of 51 patients with myeloid sarcoma who underwent allogeneic hematopoietic cell transplantation, 5-year overall survival was 47%. Remission status at the time of hematopoietic cell transplantation is an important prognostic consideration 59. Given the favorable results, consider treatment intensification with allogeneic hematopoietic cell transplantation for patients with myeloid sarcoma and concurrent marrow involvement together with other patient-related factors mentioned in the previous section, including standard age- and cytogenetic- and molecular-based risk profiling. Most often, the approach is to treat with conventional AML-type chemotherapy 60, with regimen choice and dosing following standard age- and cytogenetic-based risk profiling 61. In clinical practice, consider radiation therapy in these instances in which less than a complete response is achieved with chemotherapy because incomplete myeloid sarcoma response after chemotherapy represents a significant risk for early bone marrow relapse after therapy 14.
Isolated myeloid sarcoma at relapse is rare and often heralds systemic relapse. The median time to marrow relapse in this setting is ∼ 7 months 62. Treatment strategies are dependent on whether the patient relapsed after chemotherapy alone or after hematopoietic cell transplantation. For patients who have relapsed after chemotherapy alone, experts often use a strategy of reinduction chemotherapy and radiation therapy to the tumor. There is no standard chemotherapy regimen for relapsed AML, and the approach would be to select a regimen that would have applied to relapsed AML. Experts often recommend hematopoietic cell transplantation, although its potential benefits in this setting are unclear. As the optimal treatment is not defined, consider entry into a clinical trial if relapsed myeloid sarcoma is included among the eligibility criteria.
Myeloid sarcoma after hematopoietic cell transplantation has conventionally been considered the first manifestation of relapsed systemic disease; however, rare cases of isolated myeloid sarcoma after hematopoietic cell transplantation have been described 63. The outcome of these patients is poor, and there is no standard management in this setting. Experts judge each of these patients individually, and their approach may include donor lymphocyte infusion 64, tapering of immunosuppression if tolerated, or investigational agents if patients are eligible. Experts also consider radiation therapy mostly a palliative modality, particularly after hematopoietic cell transplantation in which further chemotherapy may be difficult to deliver. The hypomethylating agent 5-azacitidine, which can be administered after hematopoietic cell transplantation, represents an alternative strategy, although it is not adequately studied in myeloid sarcoma 65.
Systemic chemotherapy is the primary choice of treatment for both isolated myeloid sarcoma and myeloid sarcoma with simultaneous bone marrow involvement. This is largely due to the fact that even if there is no primary bone marrow involvement, isolated or primary myeloid sarcoma ultimately gives rise to AML in majority of the cases 66. Consequently, the chemotherapy regimens for myeloid sarcoma generally follow the same protocol as AML. All these regimens mainly include cytarabine with fludarabine, idarubicin, or both. In some instances, granulocyte colony-stimulating factor (G-CSF), daunorubicin and cyclophosphamide are also used 67. In particular, combination therapy with cytarabine and daunorubicin has been demonstrated to achieve complete remission in ∼65% of myeloid sarcoma patients. In addition, chemotherapy has also shown to be effective in attenuating AML development in isolated myeloid sarcoma cases (∼71%) in both adult and pediatric population 68. However, at present there is not enough data to identify a specific chemotherapy plan that is beneficial for myeloid sarcoma.
In some instance, radiation is also used as a part of the treatment plan for myeloid sarcoma. However, existing data does suggest that radiation alone may not be sufficient enough to completely eradicate myeloid sarcoma. Study conducted by Bakst et al. 66 has demonstrated that patients with isolated myeloid sarcoma generally respond better to systemic chemotherapy compared to radiotherapy. In addition, there is also no conclusive data demonstrating that radiotherapy in myeloid sarcoma alone can prevent the development of systemic leukemia involving bone marrow (∼40%). Consequently, in most cases radiation is used in combination with chemotherapy in treating myeloid sarcoma 69.
Bone marrow transplantation
Allogenic stem cell transplantation has also been demonstrated to be beneficial in treating isolated myeloid sarcoma. Consequently, many investigators/clinicians considered allogenic stem cell transplantation as a primary line treatment following remission in myeloid sarcoma patients 70. However, in a retrospective study, Chevallier et al. 70 have showed that there is no difference in 5-year survival rate in patients with isolated or myeloid sarcoma with leukemia when treated with allogenic stem cell transplantation. In both the cases, the average survival was ∼48% for 5-year survival. In a different study, Pileri et al. 71 showed that myeloid sarcoma patients receiving transplantation demonstrated a better overall survival rate (∼70%), than patients who did not receive transplantation (0%) as a part of the treatment plan. In subgroup analysis, transplantation did not display any biasness depending on age, tumor site, timing of diagnosis etc. 71.
Taken together, these reports do suggest that transplantation should be considered as a part of the consolidation therapy following remission in both isolated and leukemic myeloid sarcoma in adult and pediatric patients. However, one should be cautious as there are reports of manifestation of myeloid sarcoma post allogenic stem cell transplantation, most likely due to reduced graft-versus-leukemia state at extramedullary sites 72.
At present, there is not enough data in the field to make an informed choice for the best course of treatment for different variants of myeloid sarcoma. Based on the existing data, it is reasonable to consider systemic chemotherapy as the best course of action, in association with radiotherapy and allogenic stem cell transplantation depending on the bone marrow involvement. Given the fact that most of the reports are isolated, single center analysis with small patient pool, it is not possible to develop a consensus therapeutic regimen. To achieve such myeloid sarcoma specific therapy, large multicenter collaboration and development of prospective clinical trials is imperative.
Myeloid sarcoma prognosis
Data on the prognostic significance of myeloid sarcoma are limited. Although the presence of extramedullary leukemia may be associated with a poor prognosis and shorter survival 36, 5-year survival rates for patients with myeloid sarcoma range between 20% and 30%, which appear similar to AML in general 73. The prognostic significance of cytogenetic alterations in the presence of myeloid sarcoma is not fully understood. Although the presence of translocation t(8;21) is associated with a relatively good prognosis when treated with standard induction and intensive consolidation chemotherapy, it remains unclear whether this favorable prognosis remains in the presence of extramedullary leukemia because there are conflicting reports 74. Byrd et al 75 analyzed 84 AML patients with t(8;21) and reported that those with extramedullary leukemia had significantly worse survival, which in part could have been the result of including a high proportion of patients with spinal or meningeal involvement. In a later study of 20 patients with isolated myeloid sarcoma by Tsimberidou et al 57, the presence of cytogenetic abnormalities, specifically abnormalities in chromosome 8, appeared to confer a worse outcome, although this was not statistically significant. However, a more recent study by the same authors 76 helped clarify this issue to some degree by comparing outcomes in 16 patients with isolated myeloid sarcoma with those of a large cohort of AML who underwent standard treatment. When matching for age and cytogenetics in 14 patients, isolated myeloid sarcoma was associated with improved event-free and overall survival when treated with anti-AML chemotherapy. Until we have more definitive data, experts consider myeloid sarcoma an additional poor prognostic factor in the overall evaluation of AML.
The presence of skin involvement has been suggested to be a marker of aggressive disease and poor outcome with shortened survival 77. However, a more contemporary study of 381 consecutive AML patients did not find that the presence of leukemia cutis conferred a statistically significant worse response to treatment or shortened survival 78. Notably, there were trends toward shorter disease remission duration in patients with leukemia cutis, which did not achieve significance probably because of the low number of patients 78. Experts consider leukemia cutis a marker of aggressive disease that can be difficult to control and patients prone to extramedullary leukemia relapses.References
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