Gelatinous Marrow Transformation in Chronic Myeloid Leukemia Post-Dasatinib Treatment: A Case Report with Review of Literature

Abstract

Gelatinous marrow transformation (GMT) is characterized by accumulation of extracellular gelatinous substances such as mucopolysaccharides, fat cell atrophy, and focal loss of hematopoietic cells. It is a rare disorder of unknown pathogenesis. Anorexia nervosa, acute febrile state, acquired immunodeficiency syndrome, heart failure, lymphomas, and carcinomas are some of the entities associated with GMT. A 57-year-old male patient presented with abdominal distension of 1-month duration. He was diagnosed as chronic myeloid leukemia (CML) and treated with imatinib. Repeat testing 2 years later revealed a normal hemogram. However, in view of his BCR::ABL1 levels of 17%, he was switched to dasatinib. Patient presented with fever, fatigue, and reduced appetite 4 months later. Hemogram revealed pancytopenia. Bone marrow examination showed a hypocellular marrow with trilineage suppression and gelatinous transformation. GMT in CML patients' posttherapy is a rare encounter. It is essential to identify this clinical scenario for optimal patient management and monitoring progression of disease.

Keywords

dasatinib - gelatinous marrow transformation - chronic myeloid leukemia - case report

Introduction

Gelatinous marrow transformation (GMT) is characterized by the presence of extracellular gelatinous material such as mucopolysaccharides that are rich in hyaluronic acid admixed with fat cell atrophy and focal loss of hematopoietic cells.[1] It is considered a rare disorder with unclear pathogenesis. GMT is found to be associated with acute febrile state, anorexia nervosa, acquired immunodeficiency syndrome, lymphomas, and carcinomas. Chronic myeloid leukemia (CML), a myeloproliferative neoplasm characterized by the presence of BCR::ABL1 fusion gene, causes tyrosine kinase to be constitutively active. This leads to increased cell proliferation and a reduction in apoptosis. Imatinib mesylate, a tyrosine kinase inhibitor (TKI), is the first-line drug used for treatment in patients with CML. Second-line drugs used in case of treatment failure or resistance include dasatinib, bosutinib, and nilotinib. One of the most common toxic effects of the use of these TKIs is myelosuppression leading to pancytopenia. Their association with GMT, however, is rare.

Case Report

Here, we report a 57-year-old male patient who presented with abdominal distension of 1-month duration. On evaluation, the total leucocyte count was 4.77 × 10³/µL with 8% blasts. Expression of BCR::ABL evaluated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) at diagnosis was 48.45%. He was, hence, diagnosed with CML in chronic phase. Bone marrow examination at this juncture showed panmyelosis. The patient was administered imatinib 400 mg once a day. He was started simultaneously on febuxostat and hydroxyurea. He was on regular follow-up and was compliant with chemotherapy. The patient did not present with any symptoms in the first 2 years. Complete blood counts that were done every month were in the normal range. At the end of the first year, bone marrow examination and qRT-PCR were done. At the end of 2 years, repeat RT-PCR was done and BCR::ABL1 expression of 17% was reported. TKI mutation studies were not done. As he did not meet the molecular response criteria, he was switched to second-line TKI, dasatinib.

Four months later, the patient presented with fever, fatigue, and reduced appetite. This time the patient had pancytopenia. The possible differential diagnoses considered for pancytopenia at this stage were myelosuppression as a complication of TKI, CML with impending blast crisis, aplastic anemia, and the rare GMT. Bone marrow examination revealed hypocellular marrow with trilineage suppression. The marrow showed presence of gelatinous material with evidence of fat atrophy and loss of hematopoietic cells. GMT was confirmed by Alcian blue stain at pH 2.5 ([Fig. 1]). Molecular testing for BCR::ABL was not done in the patient at this admission. Subsequently, in our patient, dasatinib was discontinued. He was discharged with stable vitals on request, after which he was lost to follow-up.

Fig. 1 Microscopic examination of bone marrow aspirate smear showing hypocellular marrow particles: (A) Leishman stain, original magnification 10 × . (B) Leishman stain, original magnification 40 × . Bone marrow biopsy showing hypocellular marrow spaces and gelatinous marrow transformation: (C) Hematoxylin and eosin stain, original magnification 10 × . (D) Hematoxylin and eosin stain, original magnification 40 × . Bone marrow biopsy with gelatinous material: (E) Alcian blue stain pH 2.5, original magnification 10 × . (F) Alcian blue stain pH 2.5, original magnification 40 × .

Discussion

Gelatinous amorphous material, a hallmark of GMT, can be highlighted by staining with Alcian blue at a pH of 2.5 that loses its positivity after pretreatment with bovine testicular hyaluronidase. This helps in differentiating GMT from the other differentials such as bone marrow edema, aplastic anemia, bone marrow necrosis, and amyloid deposits ([Table 1]).

Table 1 Differential diagnosis for GMT on bone marrow examination

Differential diagnosis	Hematopoietic elements	Adipose tissue	Additional features
Bone marrow edema	Focally decreased	Normal size and normal quantity
Bone marrow necrosis	Decreased	Decreased	Presence of marrow destruction features, viz., the pyknotic nuclei, cellular debris with abnormal eosinophilic staining of cytoplasm[3]
Aplastic anemia	Decreased	Intact
Amyloid deposition	Intact, increased plasma cells	Intact	Homogenous pink material in the interstitial tissue or vessel wall with an increase in plasma cells. Apple-green birefringence demonstrated using a polarizing microscope, on a Congo red stained section

Abbreviation: GMT, gelatinous marrow transformation.

Incidence of GMT was 0.2% in a large series of marrows reviewed by Böhm.[1] Majority were associated with malignant tumors (38%) including hematological malignancies such as Hodgkin's and non-Hodgkin's lymphoma, acute myeloid leukemia, multiple myeloma, and myelodysplastic syndrome. However, none were in association with CML. A review of literature revealed approximately eight cases of GMT secondary to imatinib therapy, where all cases were found to be of CML ([Table 2]).[2] [3] [4] [5] [6] [7] [8] [9] Dasatinib, a second-line TKI, can rarely show GMT as evidenced by literature search, which revealed only two cases, where this drug was given in a case of acute lymphoblastic leukemia and CML, respectively.[2] [8]

Table 2 Salient features of patients with GMT treated with TKI

Study	Disease	Drug	Duration	Result of stopping drug/Outcome
Sharma et al[2]	ALL	Dasatinib	1 month	No recovery, succumbed to febrile neutropenia
Ram et al[4]	2 cases of CML	Imatinib	1 year; 22 months	Not mentioned; Stopped drug and underwent bone marrow transplantation
Hermel et al[6]	CML	Dasatinib	4 years	Decrease in GMT. Resurgence of Ph+ clones
Hong et al[7]	CML	Imatinib	11 months	On review at 14 months, patient remained well and is in complete hematological remission
Chang et al[8]	CML	Imatinib	1 year, in remission for 5 years, restarted for 2 months	CML progressed, opted for hospice care
Our study	CML	Dasatinib	4 months	Lost to follow-up

Abbreviations: ALL, acute lymphoblastic leukemia; CML, chronic myeloid leukemia; GMT, gelatinous marrow transformation; Ph + , Philadelphia chromosome; TKI, tyrosine kinase inhibitor.

A retrospective study reviewing records of 683 patients diagnosed with CML on imatinib treatment, revealed cytopenia in 60 patients with only one being diagnosed as GMT.[9] Ram et al described GMT in two CML patients treated with imatinib. Theirs was one of the earliest series linking TKI treatment, imatinib, in the pathogenesis of GMT.[4] Singh et al ascertained that the presence of gelatinous transformation along with features such as an increase in plasma cells, lymphocytes, mast cells and stromal cells and an absence of capillary proliferation could indicate an impending aplastic anemia and that patients showing an aplastic condition should also be screened for GMT.[5] We did not observe these additional features in our case. Hermel et al reported a case of CML treated with dasatinib who developed GMT and advanced secondary myelodysplastic syndrome ([Table 2]). After discontinuation of TKI, repeat bone marrow biopsies in their patient revealed diminished amounts of gelatinous transformation and a resurgence of clones with Philadelphia chromosomes (Ph + clones). This was one of the first cases indicating the reversibility of GMT in 2018.[6] Reversibility of the condition could not be assessed in our case as the patient was lost to follow-up. GMT in a case of CML-chronic phase had not been reported prior to treatment with TKI therapy.[7] Probable reasons could be the lack/duration of follow-up, changes being focal, or probably uncommon.

TKI treatment inhibits active tyrosine kinase of c-KIT, PDGFRβ of tumor cells, vascular endothelial growth factor, and benign mesenchymal cells causing reduced synthesis of extracellular matrix (ECM) components and an enhanced antifibrotic activity. This reduction in ECM components or any injury to ECM can result in changes in the mesenchymal and hematopoietic cells of the bone marrow, interfering with normal hematopoiesis. All these destroy the normal architecture and functioning of the bone marrow. In advanced cancers, the increased catabolic state causes an increase in production of mucopolysaccharides. Malignant cells are also thought to produce hyaluronic acid, which fills the marrow transiently.[4]

Following up non-CML patients treated with TKI could probably help in answering the question whether GMT is a consequence of CML itself or of treatment with TKI. Additionally, drug-induced GMT can be proved in two ways. One of these would be stopping the drug, keeping the patient on follow-up until there is recovery from pancytopenia, and finding evidence of recurrent cytopenia after giving a bolus dose. Alternatively, one could also perform marrow biopsy for the evaluation of absence of GMT features after the cessation of the drug. Imatinib is the standard care in CML cases and GMT in these cases has been reported frequently. However, case reports of GMT with dasatinib therapy, a second-line drug in CML, may not be commonly reported as the drug is used only in imatinib failure or resistant cases. Awareness of such association may provide an insight into the actual incidence of GMT in patients on dasatinib.

Conclusion

Gelatinous bone marrow transformation in CML patients posttherapy with second-generation TKI is rare. GMT in CML is associated with poor prognosis and early identification aids in prompt therapy. Bone marrow examination for GMT changes in CML patients on TKI with persistent cytopenia is recommended. The possibility of the reversibility of this condition with TKI discontinuation needs to be evaluated. Detection of this uncommon entity of GMT is essential in creating an awareness for the need of alternate drugs for the treatment of CML.

Conflict of Interest

None declared.

Note

The manuscript has been read and approved by all the authors, that the requirements for authorship have been met, and we all believe that the manuscript represents honest work.

Authors' Contributions

Concept: C.B.P.

Literature search: G.K., P.V.

Data acquisition: G.K., C.B.P.

Manuscript preparation: G.K., P.V.

Manuscript editing: C.B.P.

Manuscript review: C.B.P., J.C.S.

Patient's Consent

The institutional ethics committee exempted the study from review and issued a waiver for patient written consent in view of patient identifiers/photographs not being used (Ref No: FMIEC/CCM/803/2022).

• References

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Publication History

Article published online:
04 June 2025