Aplastic anemia triggered by the Bruton tyrosine kinase inhibitor acalabrutinib in two patients with mantle cell lymphoma – a case report

doi:10.21203/rs.3.rs-3795875/v1

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Case Report

Aplastic anemia triggered by the Bruton tyrosine kinase inhibitor acalabrutinib in two patients with mantle cell lymphoma – a case report

https://doi.org/10.21203/rs.3.rs-3795875/v1

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The use of Bruton's tyrosine kinase inhibitors (BTKi) is rapidly increasing for patients with mantle cell lymphoma (MCL). Side effects reported so far are usually manageable and self-determining after dose-reduction or termination of the drug. However, here we present a new aspect of BTKi’s that needs to be taken into consideration as we report two cases of life-threatening aplastic anemia upon treatment with the BTKi acalabrutinib for MCL.

The two patients were treated with acalabrutinib as first line treatment, patient 1 for a classical MCL with moderate proliferation and patient 2 for an aggressive tumor with blastoid morphology, p53 overexpression and high proliferation rate.

Both patients had excellent tumor responses but within a few months they presented with trombocytopenia that quickly led to a fulminant pancytopenia. Acalabrutinib treatment was stopped immediately but the pancytopenia did not resolve. Investigations led to the diagnosis of the autoimmune disease aplastic anemia in both cases. Patient 1 died of neutropenic infection shortly after the diagnosis. Patient 2 was treated successfully with immunosuppression and regained near to normal blood counts, but subsequently developed relapsed MCL.

Autoimmune diseases in general are overrepresented in patients with lymphoma, and there are reports of other autoimmune anemias such as autoimmune hemolytic anemia being triggered by lymphoma treatment. Aplastic anemia however, has never previously been reported as a potential side effect of BTKi in MCL. There is a possibility that this condition is underrecognized and mistaken for progression of tumor infiltration in the bone marrow. Aplastic anemia should be taken into consideration when patients present with pancytopenia during treatment with BTKi.

mantle cell lymphoma

aplastic anemia

acalabrutinib

bruton tyrosine kinase (BTK) inhibitor

case report

Aplastic anemia (AA) is an autoimmune disease characterized by pancytopenia that was first reported in 1888 (1). In AA, the bone marrow is cell deficient without significant fibrosis or infiltration by malignant cells. Symptoms are related to the cytopenia and include bleeding, fatigue, cardiovascular symptoms and infections. Causal treatment for AA is mainly the immune suppressive drug antithymocyte globulin (ATG) in combination with ciclosporin. Allogenic stem cell transplantation can be an option for younger patients, and recently chimeric antigen receptor T-cells (CAR-T) treatment has been tried successfully in autoimmune diseases (2) but is not yet investigated in AA. In the elderly, treatment has to be individually assessed but ATG in combination with ciclosporin, or ciclosporin alone can be considered, as well as the thrombopoietin receptor agonist eltrombopag (3). Supportive treatment with blood and platelet transfusions, as well as broad spectrum antibiotics are usually needed.

Bruton's tyrosine kinase inhibitors (BTKi) have greatly improved the outcome for patients with mantle cell lymphoma (MCL)(4). The use of BTKi in MCL is rapidly increasing and new indications are approved in several hematological malignancies. BTKis are also being investigated for solid tumors such as lung and breast cancer (5). Even though side effects are usually manageable and self-terminating after dose reduction or termination of the drug, there is reason for caution.

Here we report two cases of life-threatening AA in patients with MCL upon treatment with the BTK-inhibitor acalabrutinib in Uppsala, Sweden.

Patient 1.

The first patient was a 79-year-old male who presented with growing lymph nodes in both inguinal regions. His medical history included Parkinson’s disease that had been diagnosed three years prior to the diagnosis of MCL, benign prostate hyperplasia and hypertension. He had a family history of systemic lupus erythematosus (SLE).

Computer tomography (CT) scan showed multiple enlarged lymph nodes on both sides of the diaphragm. Needle biopsy showed classical type MCL with no p53 overexpression. There was no malignant bone marrow (BM) involvement, the cell content of the BM was 40%. His performance status according to Eastern Cooperative Oncology Group (ECOG) was 0 and he had no B-symptoms.

Since he was asymptomatic, watch and wait was initially intended, but as the patient experienced increasing fatigue and clear progression of lymph nodes after two months, treatment was initiated. BM aspirate showed 0.3% clonal B-cells. CD4/CD8 ratio was 3.6 in BM and 6.2 in peripheral blood (PB).

The treatment was started with prednisone and allopurinol due to high tumor burden and sulfametoxazol/trimetoprim as prophylaxis for pneumocystis jirovecii. The patient then started with capsule acalabrutinib 100 mg x 2 in combination with rituximab (every four weeks).

At clinical evaluation after three weeks the patient felt much better and was considered to have a very good partial remission of the palpable lymph nodes.

After three months of treatment, a reduction of the platelet count was noted (74 vs previous 132 x10⁹/liter) (Fig. 1). At the same time there was a rise in the liver enzymes aspartate aminotransferase (AST) and alanine transaminase (ALT) (Fig. 1) while bilirubin remained normal. Sulfametoxazol/trimetoprim was stopped due to suspected side effect. After a few more days there was a further decline of platelet count (22 x10⁹/l), and white blood cell count (WBC) started to decline. Acalabrutinib and rituximab were paused. After an eight-day pause of acalabrutinib (and five weeks since last rituximab) the liver enzymes were normalized but peripheral blood values were still declining, with platelet count 10 x10⁹/l and WBC 0.7 x10⁹/l.

The situation was complicated by a covid-19 infection that clearly started after the first signs of pancytopenia. The patient received platelet transfusion, granulocyte colony stimulating factor (G-CSF) and nirmatrelvir/ritonavir (ten days antiviral treatment due to prolonged covid-19 infection) and the covid-19 infection was resolved with only mild respiratory symptoms.

A pre-planned CT scan was done to evaluate the effect of acalabrutinib, it showed nearly complete radiological remission of the MCL. Flow cytometry of bone marrow was performed with no malignant cells. PB CD4/CD8 ratio was 5.2, indicating low levels of CD8 + T-cells. The corresponding rate in BM was 2.7.

A few days later, the pancytopenia was further aggravated and the patient was admitted to inpatient care with neutrophil counts < 0.1 x10⁹/l, platelet count was held at acceptable levels with transfusions. The bone marrow was now aplastic, < 10% cell counts, "pronounced hypoplasia/aplasia". The few available cells had a CD4/CD8 ratio of 2.5. Parvovirus B19, cytomegalovirus (CMV), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV) were all negative. A myeloid next generation sequencing (NGS) panel was applied and showed no tumor associated mutations but a germline mutation of Neurofibromatosis-1 (NF-1).

The diagnosis of AA was established and treatment was initiated with prednisone 50 mg. Pentamidin inhalations and ciprofloxacin were added as prophylaxis due to the deep neutropenia.

A new bone marrow biopsy after additionally four weeks was noted as "white biopsy". Cell counts was 0%, flow cytometry showed CD4/CD8 rate 2.0. There were no signs of lymphoma in the bone marrow nor clinically. It was now clear that prednisone alone was insufficient to turn the situation around. Eltrombopag and ciclosporin were started but the very same day the patient developed a fever. Broad spectrum antibiotics were immediately started. Urine samples were positive for Enterococcus faecium and a CT scan of the thorax showed pneumonic infiltrates. The patient was treated intensely but his condition worsened and after six days in the intensive care unit he died from septic shock and multi- organ failure secondary to AA.

Patient 2.

Our second patient was a 77-year-old female, non-smoker, healthy. She was investigated due to gastric discomfort and diarrhea. A CT scan showed a large tumor in the lung, a tumor in the colon and multiple enlarged lymph nodes in the abdomen. She had an ECOG performance status 0 and slight B-symptoms with night sweats and a three kilogram (kg) weight loss. A colon biopsy showed MCL with blastoid morphology and p53 overexpression. Ann Arbor stage IV.

Her bone marrow had 50% cell counts, and 0,1% MCL cells by flow cytometry. The CD4/CD8 ratio was 0.5 in BM and 0.3 in PB.

The patient was started on first line treatment with acalabrutinib 100 mg x 2 in combination with rituximab (every four weeks). Acalabrutinib was given as capsules and her proton pump inhibitor was changed to H2 receptor antagonist due to risk of interaction. After one month, all gastric discomfort was gone. She experienced no symptomatic side effects, but a liver toxicity with a rise in AST and ALT (Common Terminology Criteria for Adverse Events, CTCAE, grade 3) led to two weeks pause, whereby the liver enzymes were normalized and acalabrutinib was restarted in the same dose. The timing of the different treatments in relation to WBC level is presented in Fig. 2.

One week after restarting, the patient presented with hematomas on her arms, bleeding in the vitreous body of the eye and in the macula, as well as cardiac palpitations. Her hemoglobin level was 81 g/l, WBC 1.0 x10⁹/l (Fig. 2) and platelet count < 5 x10⁹/l (Fig. 1). Acalabrutinib was stopped permanently.

Hemophagocytic lymphohistiocytosis (HLH) was suspected at first. She received platelet and erytrocyte transfusions, and G-CSF injections daily for one week. She was started on prophylactic medication with ciprofloxacin, aciclovir and sulfametoxazol/trimetoprim.

Bone marrow biopsy showed extremely cell deficient bone marrow. The few cells were analyzed with flow cytometry as 66% T-cells, 37% NK cells, 0,1% polyclonal B-cells. CMV, EBV, hepatitis, HIV, parvo-B19 were all negative. Toxicity of acalabrutinib was now suspected. Sulfametoxazol/trimetoprim was changed to pentamidin inhalation. She started prednisone 1 mg/kg. The patient was still stable, the bleedings had stopped and she had no fever. After one week of high dose steroids there was a slight improvement with WBC 2.5 x10⁹/l, neutrophil count 0.62 x10⁹/l and platelet count 42 x10⁹/l (transfusions had been given).

BM biopsy still showed aplasia with no signs of MCL and the diagnosis was established as idiosyncratic immunologic AA due to acalabrutinib.

After one month on high dose steroids the patient had a WBC of 4.1 x10⁹/l but she developed thrombocytopenia whenever prednisone was lowered below 40 mg daily, consequently eltrombopag was started. BM cell count was now 30%, with lively erythropoiesis. Hb was 95 g/l, WBC 1.0 x10⁹/l, platelet count 14 x10⁹/l. There was now also an M-component IgG kappa of 7g/l, not seen in previous samples and a very low background gamma level.

Eltrombopag initially kept thrombocyte levels acceptable, but after two months there was a higher demand for transfusions, consequently treatment with ciclosporin was started.

More than six months after discontinuation of acalabrutinib the patient still had low cell counts and manifest AA. A CT scan showed complete remission of the lymphoma in the gut, but a slight increase in the volume of the lung tumor. The tumor in the lung was irradiated with stereotactic radiation therapy (4 gray x 2 fractions = 8 gray). This resulted in a good response in the irradiated tumor, but was soon followed by growth of mediastinal and paratracheal lymph nodes. Since the blood counts were still low, radiotherapy was the only treatment that she was expected to tolerate. Thus, these lymph nodes were also irradiated with the same dose two months after the first radiotherapy. At the time of the second radiotherapy (Fig. 2, day 308), flow cytometry of peripheral blood showed tumor cells of 0.01%. CD3 + T-cells 17%, CD4/CD8 ratio 1.0. Hb 90 g/l, WBC 2.7 x10⁹/l, platelet count 27 x10⁹/l, reticulocytes 45 x10⁹/l.

One year after termination of acalabrutinib there was progression of the tumor at multiple locations. Bone marrow function was now almost normal and a de-escalation of ciclosporin was initiated with the intention to gain an immune response towards the tumor. However, despite this there was a massive progression of the tumor in the lung. With now acceptable peripheral blood values the patient was started on rasburicase and prednisone followed by bendamustine. Within less than two weeks the palpable lymph nodes at the neck had disappeared and the patient now continues on bendamustine with close monitoring of the peripheral blood values.

Here we present two cases of AA that presented within a few months after the start of the BTKi acalabrutinib. Both patients had excellent responses regarding the MCL but patient no. 1 died of complications to the AA and patient no. 2 was treated with immunosuppressive treatment and subsequently developed relapsed MCL.

The fact that AA has never previously been reported as a side effect of BTKi in MCL suggests that it is rare, but since the events were devastating for the patients we wish to raise awareness of the condition. There is also a risk that the condition is under-recognized and misinterpreted as progressive bone marrow infiltration of the tumor.

There are several reports showing connections between hematological malignancies and autoimmune hemolysis as well as AA, but this is the first report of AA potentially triggered by acalabrutinib in MCL patients. Causality is of course hard to establish, and AA might have been triggered by the MCL itself, but it is hard to disregard considering the timing in these two cases.

In the literature, there are some difficulties identifying cause of anemia as many patients are anemic due to the malignant disease itself. Autoimmune cytopenia also include the more common autoimmune hemolytic anemia (AHA) and immune thrombocytopenia (ITP), while pure red cell aplasia (PRCA), autoimmune neutropenia (AIN) and AA are less common (6).

AHA is known to be associated with chronic lymphocytic leukemia (CLL) and can emerge at any time during the disease course, as well as being triggered by start of treatment. Cytopenia coexisting with CLL at diagnosis often resolve during CLL treatment (7–9). AA has however only been reported in three out of 1750 patients (0.17%) with CLL and at even lower rates in other lymphoid malignancies. There are only a few case reports of AA in non-Hodgkin lymphomas (6) and no data on the frequency among MCL patients.

Most cases of AA in general are considered idiopathic but a higher incidence is reported in patients with other hematologic disorders (especially CLL) (7) as well as those exposed to certain drugs, including chemotherapy. Interestingly, Ramidal et al reported on two patients with AA triggered by tyrosine kinase inhibitors for chronic myeloid leukemia (CML) (10).

A common risk factor for both AA and MCL is clonal hematopoiesis which is found in about 50% of AA patients (11, 12) and 30% of pre-treatment samples in MCL (13). We have no data on clonal hematopoiesis in these two patients but a mutation in the tumor suppressor gene Neurofibromatosis type I (NF-1) was seen as a germline variant in patient no. 1. Mutations in this gene are typically associated with a developmental syndrome that can affect the renin–angiotensin system (RAS) system (14). There is also an association between mutations in this tumor suppressor gene and juvenile myelomonocytic leukemia (14), however there is no evidence of a connection to either MCL nor AA. The disease severity varies widely and there were no signs of this syndrome in our patient so it was most likely an incidental finding.

Regulatory T-cells (T-regs) play a critical role in acquired AA (15) and Xia et al provide an interesting approach to a potential mechanism for the triggering of AA by acalabrutinib. They have investigated how acalabrutinib inhibits regulatory T-cells, leading to a stronger response by cytotoxic T-cells, potentially aggravating a pre-existing autoimmunity (16). Our two patients hade opposite CD4/CD8 ratios where patient no. 1 had an unusually high ratio (representing low levels of cytotoxic T-cells) already at diagnosis while patient no. 2 had a low ratio that is commonly seen in chronic inflammation, malignant disease and age-associated morbidity (17).

There were several similarities between our two patients. Both patients were older, in their late 70s. Acalabrutinib was given as first line treatment in both patients so they were not heavily pretreated. They did not have many comorbidities nor other medications. Neither of the patients had evidence of viral infection prior to the onset of AA. Interestingly, both these patients had a slight increase in liver enzymes prior to an isolated thrombocytopenia that within a week developed into pancytopenia. We hypothesize that acalabrutinib triggered an autoimmune response towards hematopoietic stem cells that quickly led to severe AA that did not resolve despite prompt discontinuation of the treatment and initiation of prednisone. The patients were too frail for allogenous stem cell transplantation and did not show any durable response to prednisone treatment. Therefore, after some hesitation due to the risk of reactivation of the MCL, treatment was started with eltrombopag and ciclosporin according to recommendations for treatment of AA in elderly patients (3). This treatment was successful in achieving acceptable PB values in patient no. 2. As was feared, MCL progressed thereafter, but thanks to acceptable blood levels, second line treatment with bendamustine was possible.

To conclude, AA is a rare but life-threatening side effect of the BTKi acalabrutinib. Immunosuppressive treatment can be successful but there is a risk of MCL reactivation. This severe complication is a cause for concern as the use of BTKi’s is exploding, and any new cases should be closely monitored and reported.

Patient perspective

Patient 1 was hospitalized the majority of the time from AA onset to his death and he expressed that he felt unfree and ill, even before he had any alarming symptoms. Patient 2 was discharged from the hospital and could go back to her daily life, but was both physically and mentally marked by both diseases. The frequent medical check-ups were a constant reminder of her situation.

Informed consent

Both patients gave their informed consent to participate in this case report since they wanted this potentially life-threatening complication to be described and shared with other healthcare providers.

Table 1. Properties of peripheral blood and bone marrow examinations before, during and after diagnosis of aplastic anemia. “day -22” refers to the corresponding date in figure 1 and 2 and represents days from start of treatment with acalabrutinib.

Patient 1

At diagnosis of MCL (day -22)

At onset of AA (day 93)

At AA remission

Peripheral blood values

Hb 145 g/l

WBC 7.6 x10⁹/l

Neutrophil count 6.3 x10⁹/l

Platelet count 214 x10⁹/l

LDH 1.8 ukat/l (normal)

Albumin 35 g/l

Hb 112 g/l

WBC 1.2 x10⁹/l

Neutrophil count <0.1 x10⁹/l

Platelet count 15 x10⁹/l

LDH 1.4 ukat/l

Haptoglobin 1.4 g/l

Retikulocytes 53 x10⁹/l

Cell counts

PB CD4/CD8: 6.2

BM CD4/CD8: 3.6

(Low CD8, normal CD4. Normal NK cell level.)

BM cell count 40%

BM tumor cells: 0.3%

PB CD4/CD8: 5.2

BM CD4/CD8: 2.7

BM cell count: <10%

BM tumor cells: 0%

Tumor characteristics

p53: no overexpression

Morphology: classic

Ki-67: 20%

MIPI: intermediate

Virus tests

CMV, EBV, HIV and Parvo B19 were all negative

Gene analysis

Germline mutation of NF-1 (NM_000267.3:c, 4069T>A, PF13571 protein), considered possibly pathogenic.

Patient 2

At diagnosis of MCL (day -63)

At onset of AA (day 56)

At AA remission (day 435)

Peripheral blood values

Hb 110 g/l

WBC 8.7 x10⁹/l

Neutrophil count 6.7 x10⁹/l

Platelet count 430 x10⁹/l

LDH 3.2 ukat/l (normal)

Albumin 29 g/l

Hb 81 g/l

WBC 1.1 x10⁹/l

Neutrophil count <0.1 x10⁹/l

Platelet count 4 x10⁹/l

LDH 2.5 ukat/l

Triglycerides 0,51

ferritin 657 ug/l

Hb 88 g/l

WBC 5.0 x10⁹/l

Neutrophil count 4.0 x10⁹/l

Platelet count 126 x10⁹/l

LDH 7.7 ukat/l

ESR 56

CRP <5

Cell counts

PB CD4/CD8: 0.3

BM CD4/CD8: 0.5 (Low CD4 and high CD8, both within normal interval. NK cells high)

BM cell count 50%

BM tumor cells: 0.1%

Cell counts

BM cell count: <10%

BM NK cells 37%

BM tumor cells: 0%

Cell counts

PB CD4/CD8 1.0

PB tumor cells: 0.01%

Tumor characteristics

p53: overexpression >30%

Morphology: blastoid

Ki-67: 55%

MIPI: high

Virus tests

CMV, EBV, hepatitis, HIV and parvo-B19 were all negative.

Abbreviations: AA aplastic anemia; PB peripheral blood; BM bone marrow; Hb hemoglobin; WBC white blood cells; LDH lactate dehydrogenase; ESR Erythrocyte sedimentation rate; CRP C-reactive protein; NF-1 Neurofibromatosis type 1; CMV cytomegalovirus; EBV Epstein-Barr virus; HIV human immunodeficiency virus

Ethics approval and consent to participate

Not applicable

Consent for publication

Both patients gave their informed consent to participate in this case report.

Availability of data and materials

Not applicable

Competing interests

The authors declare that they have no competing interests

Funding

None

Authors' contributions

I.G. treated the patients. A.N. and I.G. reviewed the literature and wrote the manuscript. A.N. prepared the figures.

Acknowledgements

The authors would like to thank dr Eva Baecklund for reviewing the manuscript.

Authors' information (optional)

Both authors work as physicians at the oncology department at Akademiska hospital, Uppsala, Sweden.

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Journal Publication

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Aplastic anemia triggered by the Bruton tyrosine kinase inhibitor acalabrutinib in two patients with mantle cell lymphoma – a case report

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