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Abstract

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction, characterized by fatigable weakness of the extraocular, bulbar, and limb musculature; prevalence is estimated at 14 to 32 per 100,000 in North America. Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, resulting from clonal expansion of B-cells in blood, marrow, and secondary lymphoid tissues. The simultaneous presentation of MG and CLL is exceedingly rare. This article presents the case of 71-year-old man diagnosed simultaneously with MG and CLL. His MG was severe and refractory to treatment; therefore, a strategy of treating his coexisting CLL with obinutuzumab and chlorambucil was pursued. Following 6 cycles of obinutuzumab and chlorambucil, his CLL is in remission and his MG is almost entirely undetectable. This is the first case report describing the use of obinutuzumab, a novel anti-CD20 monoclonal antibody, in a patient with concurrent MG and CLL.

Keywords

Myasthenia gravis chronic lymphocytic leukemia obinutuzumab rituximab autoimmune immunotherapy

ABBREVIATIONS

AchR

Acetylcholine receptor

BAFF

B-cell-activating factor

CLL

Chronic lymphocytic leukemia

CPAP

Continuous positive airway pressure

FOXP3

Transcription factor forkhead box protein P3

ICU

Intensive Care Unit

IVIG

Intravenous immunoglobulin

Myasthenia gravis

MRC

Medical Research Council

MuSK

Muscle specific tyrosine kinase

Reference range

SOBOE

Shortness of breath on exertion

SVC

Slow vital capacity

Treg cells

Regulatory T cells

INTRODUCTION

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction, characterized by fatigable weakness of the extraocular, bulbar, and limb musculature. This condition is mediated by acetylcholine receptor (AchR) antibodies in 80-90% of patients [1]. Of the remaining patients without AchR antibodies, up to 30% have antibodies against muscle specific tyrosine kinase (MuSK) [1]. The prevalence of MG is estimated at 14 to 20 per 100,000 in the United States [2], and has been reported as high as 32 per 100,000 in parts of Canada [3]. MG affects women more than men (3 : 1) below the age of 40; over the age of 50 men are affected more than women [4]. Between the ages of 40 and 50, and during puberty, occurrence is equal [4].

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, resulting from clonal expansion of B-cells in blood, marrow, and secondary lymphoid tissues [5]. Patients typically present with incidentally discovered lymphocytosis, lymphadenopathy, cytopenias, and less commonly autoimmune phenomenon. This malignancy is relatively common, with approximately 18,960 cases of CLL diagnosed in 2016 [6]. The cumulative lifetime risk of developing CLL is estimated at 0.5–1% (roughly 1 in 200) [6]. Many patients with CLL have a median survival exceeding 10 years, making it a prevalent cancer in the general population.

The simultaneous presentation of MG and CLL is uncommon. To date, only 14 cases of concurrent MG and CLL have been reported, with simultaneous (within 1 month) diagnosis occurring in only 5 cases [7 –16]. Here we present the case of a patient diagnosed simultaneously with MG and CLL. At the time of diagnosis, no active treatment for CLL was indicated. The patient’s MG was severe, with only brief responses to treatment (refractory), therefore a strategy of treating his coexisting CLL with obinutuzumab and chlorambucil was pursued. This is the first case report describing the use of obinutuzumab, a novel anti-CD20 monoclonal antibody, in a patient with MG and CLL.

CASE

A 71 year-old right-handed man presented to hospital with progressive orthopnea, bilateral ptosis, diplopia, dysarthria, and dysphagia. He developed shortness of breath on exertion (SOBOE) approximately 1 month prior. Asymmetric, bilateral ptosis was noted 5 days after the onset of SOBOE, along with fluctuating dysarthria and dysphagia. He could not speak full sentences or chew solid food. He then developed intermittent, binocular, vertical diplopia that was worse when looking at bright lights and on right lateral gaze. All symptoms were fatigable and worse at night. He denied weakness to the extremities, had no sensory complaints, and was ambulating normally.

His medical history was significant for a recent diagnosis of CLL, Rai Stage 1. This was identified on routine bloodwork and coincided with the onset of SOBOE and bulbar symptoms. His presenting lymphocyte count was 48.3 (reference range (RR): 0.7–3.5 10⁹/L), with a normal hemoglobin and platelet count. Peripheral blood smear showed marked lymphocytosis with smudge cells; flow cytometry on peripheral blood showed the classic immunophenotype of dim CD20+/CD19+ B lymphocytes co-expressing CD5+. He had small palpable axillary lymphadenopathy but no splenomegaly. There was no specific indication for CLL treatment at presentation so a course of expectant management was recommended. Other comorbidities included hypertension, past smoking, obstructive sleep apnea for which he used nocturnal continuous positive airway pressure (CPAP) therapy, prior prostate cancer treated with prostatectomy, reflux, depression, and cataracts. Family history was non-contributory.

The patient was admitted to the Neurology ward for evaluation. Vital signs were stable. Cardiac and abdominal examinations were normal. Breath sounds were decreased to the lung bases but no adventitious sounds were heard. Slow vital capacity (SVC) was 2.45 L (predicted >3.5 L). Mental status and language testing were normal. He had nasal phonation. There was bilateral ptosis that improved with ice application; paradoxical ptosis was also noted. The left eye did not adduct fully and there was nystagmus to the right abducting eye. Diplopia was reported on right gaze. There was bilateral upper and lower facial weakness and tongue weakness. The remainder of the cranial nerve examination was normal. Bulk and tone were normal; there were no fasciculations. Strength was entirely normal to all muscle groups; however, both deltoids and biceps demonstrated fatigability. Reflexes were 2+ and symmetric. The toes were down-going. Sensation to pin and vibration was decreased to the mid-calf bilaterally; proprioception was normal. Cerebellar testing was normal. Gait was normal.

Initial investigations included normal electrolytes, creatinine, urea, calcium, phosphate, magnesium, creatine kinase, C-reactive protein, liver panel, vitamin B12, hemoglobin A1c, serum protein electrophoresis, and thyroid stimulating hormone. Lymphocyte count was 36.2; smudge cells and abnormal lymphocytes present, in keeping with CLL. Nerve conduction studies demonstrated 75–83% decrement between stimulations 1 and 4 with 3 Hz repetitive nerve stimulation of the right nasalis, consistent with MG. AchR antibody testing was positive at 3.44 nmol/L (a positive result corresponds to precipitation greater than 1 nmol/L). CT chest enhanced was negative for thymoma, but showed bulky lymphadenopathy in the axillary and retroperitoneal regions, consistent with CLL.

Intravenous immunoglobulin (IVIG) 2 g/kg divided over 5 day, prednisone 50 mg daily, and pyridostigmine 60 mg 5 times daily were started. His symptoms improved following the first dose of IVIG. By the fifth day his diplopia resolved completely and the orthopnea, ptosis, facial diplegia, and dysarthria improved considerably. SVC improved from 2.2 to 3.6 L. He was discharged from hospital 9 days after presentation on prednisone 50 mg daily and pyridostigmine 60 mg 4 times daily plus pyridostigmine SR 180 mg nightly.

Shortly after discharge his SOBOE and orthopnea returned. Two weeks later he developed profound fatigable dysphagia. Fatigable dysarthria, intermittent diplopia, bilateral ptosis, facial diplegia, and neck weakness developed over the subsequent 2 days. He re-presented to hospital (17 days after discharge) and was found to have a SVC of 1.3 L; lymphocyte count was 76.4. Neck flexor strength was rated Medical Research Council (MRC) grade 4-/5 and hip flexor strength was rated 4/5 bilaterally. There was no identifiable trigger for this decline. He was admitted to the Intensive Care Unit (ICU) for close observation, but did not require intubation. A second course of IVIG was given. Methotrexate 7.5 mg per week was started immediately following IVIG therapy, with plans to increase by 2.5 mg per week to 15 mg weekly.

Nine days after re-admission his SVC was 4.08 L and his orthopnea resolved; neck flexor strength improved. There was no ptosis, diplopia, or dysarthria at baseline; however, these symptoms re-emerged by the end of the day or after activity. Unfortunately, 4 days later he complained of generalized weakness and worsening ptosis. Neck flexor strength was rated 4/5, neck extensor 4+/5, triceps 4/5, and hip flexors 2/5. His SVC declined to 2.59 L that day. Lymphocyte count was 81. Prednisone was increased to 70 mg daily. The following day his orthopnea recurred and his diplopia worsened. A third course of IVIG was given. After the first dose his symptoms improved dramatically. By the fifth dose his orthopnea and diplopia resolved; neck flexor strength was 4+/5 and hip flexor strength was 4/5.

Three courses of IVIG were given, the last of which occurred 10 days apart. It appeared that the effects of IVIG were wearing off sooner with each subsequent course. Given the concurrent diagnosis of CLL, resulting in lymphocyte counts as high as 82.5, Hematology was consulted. Peaks in lymphocyte count coincided with worsening symptoms of MG. The patient was transferred to the Hematology ward for treatment of CLL. Methotrexate was stopped. Obinutuzumab (1, 2, 8, 15 protocol) was started; the infusion was well tolerated. Following the first dose his SVC dropped to 1.26 L from 2.6 L, his SOBOE recurred and his proximal muscle weakness worsened. A fourth course of IVIG was started; he received his second dose of obinutuzumab and his first dose of chlorambucil on that day. Profound SOBOE persisted. SVCs were consistently less than 2 L throughout IVIG therapy. CPAP was used as needed to support breathing; transfer to the ICU was not required.

Improvement was noted 1 day after completing IVIG therapy; SVCs were above 2 L. Two days later his proximal muscle weakness largely resolved, along with his SOBOE. He was discharged home and continued to receive obinutuzumab and chlorambucil as an outpatient.

Eight days after discharge he re-presented to hospital with ptosis, diplopia, difficulty chewing, and increased work of breathing. His SVC was 2.1 L and his lymphocyte count was 6.9. His symptoms continued to worsen in hospital so IVIG was started. There was modest improvement in his symptoms following IVIG; ptosis improved, difficulty chewing resolved, and work of breathing normalized. He was discharged home 10 days after admission; SVC was 2.6 L and lymphocyte count was 7.0.

The patient was seen in the Neuromuscular Clinic 2 weeks after discharge. He reported relatively stable symptoms; however, symptoms worsened on the day of chemotherapy, which carried through to the following day. He denied diplopia, dysphagia, dysarthria, and weakness. On examination, no dysarthria or shortness of breath were observed. He had bilaterally ptosis affecting the right eye more than the left. Diplopia could not be elicited with sustained up-gaze. Neck flexion was rated 4/5, deltoids 4/5 and fatigable, triceps 4+/5, and hip flexion 3/5.

Two weeks later his ptosis worsened to the point of eye closure on up-gaze, neck extension was 4-/5, deltoids 4+/5, triceps 4+/5, and hip flexion 4/5. IVIG 1 g/kg was given as a single dose, followed by 400 mg/kg weekly thereafter; pyridostigmine was increased to 90 mg 4 times daily plus pyridostigmine SR 180 mg nightly. Thirteen days later his symptoms began to improve; IVIG was increased to 500 mg/kg weekly. After 3 doses his ptosis improved significantly, neck flexion and extension were full power, deltoids were 4+/5 and fatigable, triceps were 5/5, and hip flexion was 4/5. One month later he had mild ptosis with sustained up-gaze after 10 seconds, he was otherwise completely normal on detailed retesting.

The patient remains on weekly IVIG, prednisone 70 mg daily, and pyridostigmine 90 mg 4 times daily plus pyridostigmine SR 180 mg nightly. A decision will be made shortly as to whether he will continue on obinutuzumab and chlorambucil; if so, we will refrain from adding another immunosuppressive agent. If this regimen is to be discontinued, methotrexate or rituximab will be introduced. A reduction in his other medication(s) may follow thereafter. We cannot rule out a delayed treatment effect from prednisone; however, it is our opinion that this is less likely as the patient did not improve until he received more than 4 months of prednisone therapy.

DISCUSSION

Our patient presented with symptoms of MG at the time of CLL diagnosis, before CLL-directed therapies had begun. He required 3 hospital admissions, 1 ICU admission, 5 full courses of IVIG, a 1 g/kg single dose of IVIG, and weekly IVIG thereafter for his MG. His response to IVIG was short lived, lasting only days after the completion of each cycle. Peaks in lymphocyte count coincided with worsening symptoms of MG. Having completed 6 full cycles of obinutuzumab and chlorambucil, he has attained a complete remission from his CLL. His MG has also stabilized and he is now functioning well in the community. He has not required readmission to hospital to date.

MG and CLL

MG is a well-recognized paraneoplastic phenomenon of thymomas in approximately 15% of patients; thymic follicular hyperplasia is seen in approximately 70% of patients [17]. MG occurs more frequently in lymphomas involving the mediastinum, possibly due to proximity to the thymus [18]. Our patient does not have a thymoma. The occurrence and type of extrathymic malignancies reported in patients with MG varies greatly in the literature [19]. In most cases, the diagnosis of extrathymic malignancy and MG do not occur simultaneously [19]. As a result, the ability to make associations between MG and cancer is challenging. Some authors suggest that cancer types in MG have a similar distribution to the general population [19 –21].

The simultaneous diagnosis of MG and an extrathymic malignancy is exceedingly rare, but has been reported [8 , 22]. Of this group, CLL was identified in 6 cases (including the present case) [8 , 13]. MG is a B-cell mediated disease targeting the postsynaptic membrane of the neuromuscular junction, resulting in impaired neuromuscular transmission and fewer functional AchRs. AchR antibodies are polyclonal IgG antibodies, generated in part by a T-cell dependent B-cell response [23, 24]. CLL results from clonal expansion of B-cells in blood, marrow, and secondary lymphoid tissues [5]. B-cell-activating factor (BAFF) is a member of the tumor necrosis factor ligand family that promotes B-cell maturation and survival [25]. When over-expressed, BAFF prevents B-cell apoptosis, thus contributing to malignancy and autoimmunity [25]. In general, auto-reactive antibodies rely more heavily on BAFF for survival, therefore excess BAFF selectively promotes the accumulation of these antibodies [25]. In patients with MG, serum BAFF levels are significantly higher than non-myasthenic controls; moreover, AchR antibody positive patients tend to have higher BAFF levels than seronegative patients [26, 27]. Interestingly, BAFF has been identified as a key player in malignant B-cell development and maintenance in CLL [28]. CLL cells express receptors for BAFF and may even express BAFF in an autocrine fashion to promote cell survival [29]. Both MG and CLL are characterized by deleterious B-cell production and regulation, involving BAFF specifically. The combined effects of these two conditions, when occurring simultaneously, may explain the refractory nature of our patient’s MG. Furthermore, it may explain why aggressive B-cell suppression has been the only treatment to have a lasting effect in our patient.

Autoimmune hematologic complications of CLL are relatively common (5–10%) [30]. Approximately 90% of autoantibodies are not directly produced by malignant CLL B-cells, and are polyclonal IgG antibodies [30]. T helper cell dysfunction and pathological antigen presentation have been shown to contribute to polyclonal IgG antibody production in CLL [30]. It has also been suggested that abnormal regulatory T (Treg) cells contribute to the pathogenesis of autoantibody formation in CLL, due to impaired peripheral tolerance [30, 31]. AchR antibodies are polyclonal IgG antibodies [32]. Similar to autoantibody formation in CLL, it has been proposed that dysfunctional Treg cells play a critical role in AchR antibody formation in MG [33]. Treg cells are primarily produced by the thymus; the transcription factor forkhead box protein P3 (FOXP3) is the primary regulator of this process [33]. Researchers have demonstrated that thymic Treg cells are nonfunctional in patients with MG [34]. Moreover, expression of FOXP3 has been shown to be reduced in certain cell types in MG, including Treg cells themselves [33, 34]. Altered peripheral tolerance appears to be a key factor in autoantibody formation in both CLL and MG. The simultaneous diagnosis of both conditions in our patient may represent a chance occurrence; however, the temporal association and paralleled progression of these processes suggests a pathogenic association. Immune dysregulation resulting from CLL may have potentiated the onset of MG in our patient. The additive effects of T helper cell dysfunction in the setting of CLL, and nonfunctional Treg cells in MG, may have contributed to his intractable clinical course.

Rituximab for MG

Current immunosuppressive treatment options for MG include corticosteroids and agents such as azathioprine, mycophenolate mofetil, and cyclosporine, among others [35]. Despite treatment, some patients have refractory disease that is not responsive to first line immunosuppressive agents. Rituximab is a chimeric mouse-human IgG1-kappa monoclonal antibody that depletes B-cells by binding CD20 and initiating complement-dependent cytotoxicity [36]. As the pathogenesis of MG is influenced by auto-reactive B-cells, targeted drug therapy may be appropriate [37]. Rituximab primarily acts by depleting the precursors of plasma cells; it may also influence T-cell response [37]. The use of rituximab for refractory MG was first reported in 2000 [38]; there have been a number of publications since then describing its use in this population [39 –41].

Obinutuzumab versus rituximab

CD20 is a ubiquitous cell surface marker on mature B-cells that has become a site for directed therapy in hematologic malignancies and autoimmune diseases [42]. Rituximab and obinutuzumab are both anti-CD20 monoclonal antibodies; however, their mechanisms of action differ with respect to how they bind their epitope [42]. Type I CD20 monoclonal antibodies, such as rituximab, promote complement-dependent cytotoxicity, apoptosis, and to a lesser extent antibody dependent cellular cytotoxicity [42, 43]. Conversely, Type II CD20 monoclonal antibodies, such as obinutuzumab, do not readily activate complement; instead they promote antibody dependent cellular cytotoxicity, phagocytosis, and non-apoptotic (caspase-independent) direct cell death [42, 43]. In vivo studies have shown higher efficacy B-cell depletion and antitumor activity with obinutuzumab compared to rituximab [43]. In a landmark randomized controlled trial involving 781 patients with previously untreated CLL and co-existing conditions, obinutuzumab plus chlorambucil was found to be superior to rituximab plus chlorambucil with respect to progression-free survival (26.7 versus 15.2 months; P < 0.001) [44]. Apart from an increase in infusion-related reactions, typically occurring in cycle one, obinutuzumab plus chlorambucil had a similar toxicity profile compared to rituximab plus chlorambucil in this study [44]. As such, this novel anti-CD20 antibody has become the preferred treatment for frail patients with CLL. The use of chlorambucil, a DNA alkylating agent, in select patients with MG has been described elsewhere [45, 46]. It is compelling to consider the other clinical applications of obinutuzumab in place of rituximab in autoimmune conditions, such as MG; however, clinical trials are required before obinutuzumab can be considered in this population.

CONCLUSION

The case of a 71-year-old man diagnosed simultaneously with MG and CLL has been described herein, representing the sixth case of this nature to be reported to date. The patient’s MG was severe, with only brief responses to treatment; therefore, a strategy of treating his coexisting CLL with obinutuzumab and chlorambucil was pursued. Following 6 cycles of obinutuzumab and chlorambucil, his CLL is in remission and his MG is almost entirely undetectable. This is the first case report describing the use of obinutuzumab, a novel anti-CD20 monoclonal antibody, in a patient with concurrent MG and CLL.

CONFLICTS OF INTEREST

The authors have no conflicts of interest to report.

FINANCIAL SUPPORT

None.

Footnotes

ACKNOWLEDGMENTS

None.

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Obinutuzumab Plus Chlorambucil in a Patient with Severe Myasthenia Gravis and Chronic Lymphocytic Leukemia

Abstract

Keywords

ABBREVIATIONS

INTRODUCTION

CASE

DISCUSSION

MG and CLL

Rituximab for MG

Obinutuzumab versus rituximab

CONCLUSION

CONFLICTS OF INTEREST

FINANCIAL SUPPORT

Footnotes

ACKNOWLEDGMENTS

References