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://www.thejh.org

Case Report

Volume 11, Number 6, December 2022, pages 223-232

Thymoma With Triple Threat: Pure Red Cell Aplasia, Autoimmune Hemolytic Anemia, and T-Cell Large Granular Lymphocytic Leukemia

Figure 1. Extensive spread of right pleural-based soft tissue neoplasm. Very large right pleural effusion with secondary leftward mediastinal and tracheal shift. Partial collapse of right lung with air bronchograms.

Figure 2. Hemoglobin, white blood cell (WBC), and platelet count trends throughout the clinical course. ATG: anti-thymocyte globulin; G-CSF: granulocyte colony-stimulating factor; IVIG: intravenous immunoglobulin; PAC: cisplatin, doxorubicin, and cyclophosphamide.

Figure 3. Bone marrow biopsy from March 2017. Description of bone marrow biopsy: Markedly hypocellular with cellularity 10-20%. Near absence of granulopoiesis with occasional blastic cells present but not increased. Erythropoiesis is decreased with very rare erythroids and some dysplasia. Increased small mature lymphocytes were noted. Findings were overall suggestive of a bone marrow failure syndrome. Description of bone marrow aspirate: Granulopoiesis essentially absent with a few scattered blasts seen. Erythroids are very rare, and some are dysplastic. Megakaryocytes are adequate to mildly increased with normal morphology. Lymphocytes are increased.

Figure 4. Bone marrow biopsy from June 2018. Description of bone marrow biopsy: Hypercellular with cellularity 70%. Myelopoiesis is increased with full maturation. Erythropoiesis is mildly increased with erythroid islands. Megakaryopoiesis is mildly increased with clustering and range of maturation. Interstitial lymphocytosis and scattered small lymphohistiocytic aggregates identified. Description of bone marrow aspirate smear: Lymphocytosis is present. Frequent small lymphoid cells have round to oval nuclei, compact chromatin and scant to moderately abundant cytoplasm with azurophilic granules. Granulopoiesis and erythropoiesis are normal.

**Table 1.** Key Laboratory Findings at Presentation of PRCA and AIHA
Labs	Result	Reference range
AIHA: autoimmune hemolytic anemia; PRCA: pure red cell aplasia; WBC: white blood cell; RBC: red blood cell; MCV: mean corpuscular volume; Ig Ser QN: quantitative serum immunoglobulins; Ig: immunoglobulin.
WBC count (× 10³/µL)	6.7	3.6 - 10.6
RBC count (× 10⁶/µL)	1.89	3.71 - 5.17
Hemoglobin (g/dL)	6.1	12.0 - 15.0
Hematocrit (%)	16.7	35.0 - 49.0
MCV (fL)	88.3	81.0 - 99.0
Platelet count (× 10³/µL)	153	150 - 450
Reticulocyte count (%)	< 0.1	0.5 - 2.5
Absolute reticulocyte count (cells/µL)	1.5	21.0 - 115.0
Reticulocyte index	0.02	≥ 2.0 adequate response
Haptoglobin (mg/dL)	< 6.0	30.0 - 200.0
Total bilirubin (mg/dL)	0.7	0.3 - 1.2
Erythropoietin (mIU/mL)	730.9	2.6 - 18.5
Direct antiglobulin test IgG	Positive
Direct antiglobulin test C3	Positive
Autoantibody	Warm
Ig Ser QN (mg/dL)
IgG	813	700 - 1,500
IgM	66	60 - 300
IgA	86	60 - 400
Tetanus toxoid IgG (IU/mL)	2.02	Immune if ≥ 0.01 IU/mL
Diphtheria toxoid IgG (IU/mL)	0.02	Immune if ≥ 0.01 IU/mL

Table 1. Key Laboratory Findings at Presentation of PRCA and AIHA

Labs

Result

Reference range

AIHA: autoimmune hemolytic anemia; PRCA: pure red cell aplasia; WBC: white blood cell; RBC: red blood cell; MCV: mean corpuscular volume; Ig Ser QN: quantitative serum immunoglobulins; Ig: immunoglobulin.

WBC count (× 10³/µL)

6.7

3.6 - 10.6

RBC count (× 10⁶/µL)

1.89

3.71 - 5.17

Hemoglobin (g/dL)

6.1

12.0 - 15.0

Hematocrit (%)

16.7

35.0 - 49.0

MCV (fL)

88.3

81.0 - 99.0

Platelet count (× 10³/µL)

153

150 - 450

Reticulocyte count (%)

< 0.1

0.5 - 2.5

Absolute reticulocyte count (cells/µL)

1.5

21.0 - 115.0

Reticulocyte index

0.02

≥ 2.0 adequate response

Haptoglobin (mg/dL)

< 6.0

30.0 - 200.0

Total bilirubin (mg/dL)

0.7

0.3 - 1.2

Erythropoietin (mIU/mL)

730.9

2.6 - 18.5

Direct antiglobulin test IgG

Positive

Direct antiglobulin test C3

Positive

Autoantibody

Warm

Ig Ser QN (mg/dL)

IgG

813

700 - 1,500

IgM

60 - 300

IgA

60 - 400

Tetanus toxoid IgG (IU/mL)

2.02

Immune if ≥ 0.01 IU/mL

Diphtheria toxoid IgG (IU/mL)

0.02

Immune if ≥ 0.01 IU/mL

**Table 2.** Cases of Thymoma-Associated PRCA Treated With Octreotide +/- Corticosteroids
References	Zaucha et al, 2007 [10]	Larroche et al, 2000 [11]	Palmieri et al, 1997 [9]
PO: per os; PRCA: pure red cell aplasia; IVIG: intravenous immunoglobulin; BID: twice a day; TID: three times a day; WHO: World Health Organization. ^aCorticosteroids combined with octreotide were contraindicated due to high risk of gastrointestinal bleeding.
Age	35	75	56
Sex	Female	Male	Female
Time between diagnoses	4 - 6 months	Concurrent	2 - 3 months
Hemoglobin at presentation (g/dL)	8.2	2.8	5.8
Reticulocyte count at presentation (%)	Information not available	0	Information not available
Transfusion dependence; frequency	Yes, frequency: 2 - 3 weeks	Yes, frequency: 1 week	Yes, frequency not specified
WHO histology	B1/B2	B1/B2	B1/B2
Masaoka Koga staging	IVB	I	IIIB
Thymectomy	No	Yes	No
Response to thymectomy	Thymectomy not performed	Remained transfusion-dependent	Thymectomy not performed
Chemotherapy	Doxorubicin, cisplatin, cyclophosphamide, vincristine (6 cycles)	None	Cisplatin, prednisone, cyclophosphamide (6 cycles)
	Cisplatin and etoposide (3 cycles)
	Ifosfamide (6 cycles)
Other treatments	Recombinant human erythropoietin, duration: 4 months	Prednisone PO 1 mg/kg/day, duration: 1 month	Prednisone PO 1 mg/kg/day, duration: 1 month
	Octreotide 20 mg IM q28d, duration: 3 months^a	Octreotide 0.5 mg, subcutaneous TID + prednisone PO 0.7 mg/kg/day, duration: 1 month	Octreotide 0.5 mg subcutaneous TID + prednisone PO 0.6 mg/kg/day, duration: not specified
		IVIG 0.4 g/kg/day, duration: 5 days
Outcomes	No response to any round of chemotherapy	No response to single agent prednisone. Reticulocyte count 0%.	No response to any round of chemotherapy.
		No response to prednisone with octreotide. Reticulocyte count 0% and patient remained transfusion-dependent.	With single agent prednisone, hemoglobin increased from 5.8 to 7.8 g/dL but patient remained transfusion-dependent.
	No response to erythropoietin
	After 3 months of octreotide, hemoglobin normalized, and bone marrow biopsy showed erythroid reconstitution.	3 weeks after treatment with IVIG, hemoglobin increased from 7.0 to 10.8 g/dL. Reticulocyte count 2.0% and patient no longer required transfusions.	After 1 month of octreotide with prednisone, hemoglobin increased, and patient no longer required transfusions. After 15 months, patient was in complete remission with no evidence of thymoma on imaging.
	Patient remains in complete remission 1 year later.
		Patient remains in complete remission > 21 months later.	Patient remains in complete remission > 3 years later. Continues to receive octreotide (0.5 mg BID) and prednisone (0.2 mg/kg/day).

Table 2. Cases of Thymoma-Associated PRCA Treated With Octreotide +/- Corticosteroids

References

Zaucha et al, 2007 [10]

Larroche et al, 2000 [11]

Palmieri et al, 1997 [9]

PO: per os; PRCA: pure red cell aplasia; IVIG: intravenous immunoglobulin; BID: twice a day; TID: three times a day; WHO: World Health Organization. ^aCorticosteroids combined with octreotide were contraindicated due to high risk of gastrointestinal bleeding.

Age

Sex

Female

Male

Female

Time between diagnoses

4 - 6 months

Concurrent

2 - 3 months

Hemoglobin at presentation (g/dL)

8.2

2.8

5.8

Reticulocyte count at presentation (%)

Information not available

Transfusion dependence; frequency

Yes, frequency: 2 - 3 weeks

Yes, frequency: 1 week

Yes, frequency not specified

WHO histology

B1/B2

Masaoka Koga staging

IVB

IIIB

Thymectomy

Yes

Response to thymectomy

Thymectomy not performed

Remained transfusion-dependent

Thymectomy not performed

Chemotherapy

Doxorubicin, cisplatin, cyclophosphamide, vincristine (6 cycles)

None

Cisplatin, prednisone, cyclophosphamide (6 cycles)

Cisplatin and etoposide (3 cycles)

Ifosfamide (6 cycles)

Other treatments

Recombinant human erythropoietin, duration: 4 months

Prednisone PO 1 mg/kg/day, duration: 1 month

Octreotide 20 mg IM q28d, duration: 3 months^a

Octreotide 0.5 mg, subcutaneous TID + prednisone PO 0.7 mg/kg/day, duration: 1 month

Octreotide 0.5 mg subcutaneous TID + prednisone PO 0.6 mg/kg/day, duration: not specified

IVIG 0.4 g/kg/day, duration: 5 days

Outcomes

No response to any round of chemotherapy

No response to single agent prednisone. Reticulocyte count 0%.

No response to any round of chemotherapy.

No response to prednisone with octreotide. Reticulocyte count 0% and patient remained transfusion-dependent.

With single agent prednisone, hemoglobin increased from 5.8 to 7.8 g/dL but patient remained transfusion-dependent.

No response to erythropoietin

After 3 months of octreotide, hemoglobin normalized, and bone marrow biopsy showed erythroid reconstitution.

3 weeks after treatment with IVIG, hemoglobin increased from 7.0 to 10.8 g/dL. Reticulocyte count 2.0% and patient no longer required transfusions.

After 1 month of octreotide with prednisone, hemoglobin increased, and patient no longer required transfusions. After 15 months, patient was in complete remission with no evidence of thymoma on imaging.

Patient remains in complete remission 1 year later.

Patient remains in complete remission > 21 months later.

Patient remains in complete remission > 3 years later. Continues to receive octreotide (0.5 mg BID) and prednisone (0.2 mg/kg/day).

**Table 3.** Cases of Thymoma With PRCA and AIHA
References	Current case	Wang et al, 2020 [26], case 1	Wang et al, 2020 [26], case 2	Wang et al, 2020 [26], case 3	Wang et al, 2020 [26], case 4
RBC: red blood cell; WBC: white blood cell; PRCA: pure red cell aplasia; AIHA: autoimmune hemolytic anemia. WHO: World Health Organization. ^aResearchers did not specify whether corticosteroids or any other treatments were given.
Timing	Concurrent	Concurrent	Concurrent	Concurrent	Concurrent
Age at diagnosis of thymoma (years)	41	65	38	45	53
Sex	Female	Female	Male	Male	Female
Hemoglobin pre-thymectomy (g/dL)	6.1	3.9	7.3	6.5	8.5
Reticulocyte count pre-thymectomy (%)	< 0.1	0.2	0.4	0.3	0.4
RBC count pre-thymectomy (× 10⁶/µL)	1.89	1.07	2.34	Information not available	Information not available
Total bilirubin; indirect bilirubin (mg/dL)	0.4; information not available	1.6; 1.2	1.5; 1.0	1.5; 1.0	0.8; 0.5
Erythropoietin (mIU/mL)	731	> 797	630	Information not available	Information not available
Lactate dehydrogenase (U/L)	Information not available	293	290	Information not available	Information not available
IgG direct antiglobulin test	+	+	+	+	+
C3 direct antiglobulin test	+	+	+	+	+
WHO histology	B2	B2 + B3	AB	AB	B2
Masoaka Koga staging	IVA	III	I	IIA	I
Thymectomy	Yes (delayed)	Yes	Yes	Yes	Yes
Treatments	Corticosteroids, octreotide	Corticosteroids (without improvement) followed by thymectomy	Thymectomy only	Thymectomy only^a	Thymectomy only^a
Outcomes	Normalization of hemoglobin	Normalization of hemoglobin post-thymectomy	Normalization of hemoglobin post-thymectomy	Normalization of hemoglobin post-thymectomy	Normalization of hemoglobin post-thymectomy

Table 3. Cases of Thymoma With PRCA and AIHA

References

Current case

Wang et al, 2020 [26], case 1

Wang et al, 2020 [26], case 2

Wang et al, 2020 [26], case 3

Wang et al, 2020 [26], case 4

RBC: red blood cell; WBC: white blood cell; PRCA: pure red cell aplasia; AIHA: autoimmune hemolytic anemia. WHO: World Health Organization. ^aResearchers did not specify whether corticosteroids or any other treatments were given.

Timing

Concurrent

Age at diagnosis of thymoma (years)

Sex

Female

Male

Female

Hemoglobin pre-thymectomy (g/dL)

6.1

3.9

7.3

6.5

8.5

Reticulocyte count pre-thymectomy (%)

< 0.1

0.2

0.4

0.3

0.4

RBC count pre-thymectomy (× 10⁶/µL)

1.89

1.07

2.34

Information not available

Total bilirubin; indirect bilirubin (mg/dL)

0.4; information not available

1.6; 1.2

1.5; 1.0

0.8; 0.5

Erythropoietin (mIU/mL)

731

> 797

630

Information not available

Lactate dehydrogenase (U/L)

Information not available

293

290

Information not available

IgG direct antiglobulin test

C3 direct antiglobulin test

WHO histology

B2 + B3

Masoaka Koga staging

IVA

III

IIA

Thymectomy

Yes (delayed)

Yes

Treatments

Corticosteroids, octreotide

Corticosteroids (without improvement) followed by thymectomy

Thymectomy only

Thymectomy only^a

Outcomes

Normalization of hemoglobin

Normalization of hemoglobin post-thymectomy

**Table 4.** Overview of Diagnoses, Treatments, and Outcomes
Diagnosis	Treatment	Outcome
Thymoma	Cisplatin, doxorubicin, cyclophosphamide	Stable disease for approximately 35 months, progression required thymectomy
Pure red cell aplasia	Octreotide and methylprednisolone	Partial remission
Autoimmune hemolytic anemia	Octreotide and methylprednisolone	Remission
Neutropenia, presumed autoimmune in origin	Anti-thymocyte globulin, tacrolimus, methylprednisolone, granulocyte colony stimulating factor, Intravenous immunoglobulin	Partial remission
T-cell large granular lymphocytic leukemia	Methotrexate	Remission

Table 4. Overview of Diagnoses, Treatments, and Outcomes

Diagnosis

Treatment

Outcome

Thymoma

Cisplatin, doxorubicin, cyclophosphamide

Stable disease for approximately 35 months, progression required thymectomy

Pure red cell aplasia

Octreotide and methylprednisolone

Partial remission

Autoimmune hemolytic anemia

Octreotide and methylprednisolone

Remission

Neutropenia, presumed autoimmune in origin

Anti-thymocyte globulin, tacrolimus, methylprednisolone, granulocyte colony stimulating factor, Intravenous immunoglobulin

Partial remission

T-cell large granular lymphocytic leukemia

Methotrexate

Remission