Chandra Diwakarla, BSc (Hons), MBBS

Patients receiving chemotherapy for various malignancies are at risk of immunosuppression, which can lead to infective complications resulting in delayed therapy and potential progression of disease. Newer agents are now available for the management of castrate-resistant, metastatic prostate cancer, which have shown improved outcomes in progression-free survival and overall survival, and are particularly advantageous in elderly patients who would not otherwise tolerate traditional chemotherapy. These agents work on steroidogenesis pathways and do not affect immune function. We describe 3 cases whereby significant septic complications occurred in the setting of abiraterone use that were associated with hypogammaglobulinemia.

A 77-year-old gentleman who commenced abiraterone in September 2014 after developing castrate- resistant prostate cancer following prior antiandrogen therapy. He developed sepsis with minimal to no improvement despite empiric intravenous antibiotics. The patient ultimately required immunoglobulin therapy with intravenous Intragam (IVIg). He subsequently opted for palliation and died.

A 73-year-old gentleman with castrate-resistant prostate cancer following antiandrogen therapy from 2006 to 2014. After beginning abiraterone in December 2014 he developed recurrent fevers requiring repeat admissions and was found to be hypogammaglobulinemic. He was started on IVIg with improvement in symptoms and has been able to continue abiraterone with ongoing IVIg support.

A 78-year old gentleman with Gleason score 9 prostate cancer who responded well to abiraterone, but later presented with sepsis of unknown source and was subsequently found to be hypogammaglobulianemic.

Prostate cancer can now be treated with a wide range of options that are associated with improved outcomes. To date, there have not been any reported cases of immunodeficiency associated with newer available agents such as abiraterone. The above cases highlight the occurrence of infection secondary to hypogammaglobulinemia in patients being treated with abiraterone and may represent a complication that needs to be considered in an already vulnerable population.

Prostate cancer is the most common solid organ malignancy in men in Australia.

Androgens are the predominant growth factor for prostate cancer, and inhibition of androgenic pathways serves as the major focus for treatment of advanced disease. Metastatic prostate cancer progressing after initial hormonal manipulation ie, castrate-resistant disease, was traditionally treated with cytotoxic drugs that were associated with significant treatment-related toxicities. Novel anti-androgen agents such as abiraterone and enzalutamide have been demonstrated to improve survival in both the pre and post-chemotherapy setting

and are considered to have a reasonable toxicity profile.

While traditional anti-androgen approaches have aimed at lowering androgen concentrations they often result in castrate-resistant/refractory disease. Newer agents such as abiraterone act by inhibiting enzymes expressed in testicular, adrenal, and prostatic tumor tissue, which would normally facilitate the conversion of pregnenolone and progesterone to their active derivatives, as well as allow for the formation of dehyroepiandrosterone (DHEA) and androstenedione, which are not only important androgens, but also function as precursors for testosterone. The inhibition of these processes by abiraterone has resulted in dramatic improvements when treating castrate-resistant disease, however, they are associated with cardiac and liver abnormalities. Apart from these side effects, abiraterone has been associated with other toxicities including sepsis, however, not in the context of immunosuppression via hypogammaglobulinemia.

The patient population most often treated with therapies like abiraterone are usually considered unfit to receive chemotherapy or have progressed through multiple previous lines of treatment, and may therefore represent a more vulnerable group in terms of risk of deterioration. Currently, these drugs have been accepted as the more tolerable approach for such patients, however, the cases discussed here describe 3 instances where recurrent infections occurred following commencement of abiraterone in which all patients were found to be hypogammaglobulinaemic.

A 77-year-old man diagnosed with Gleason score 9 prostate cancer in 2010 was referred to medical oncology for presumed metastatic disease in 2013. He had originally undergone radical radiation therapy followed by leuprorelin acetate, a gonadotrophin- releasing hormone (GnRH) agonist, every 3 months with a good biochemical response evidenced by a reduction in prostate-specific antigen (PSA) from 12 to 0.04 &mu;g/L. In 2013, the PSA steadily increased from a normal baseline to 43 &mu;g/L with an approximate doubling time of <2 months.

Despite this, he remained relatively asymptomatic and further investigations including CT chest, abdomen, and pelvis revealed multiple bone metastases, but no other sites of disease. His relevant past medical history included chronic liver disease/cirrhosis secondary to autoimmune hepatitis, which was managed with a combination of azathioprine 100 mg daily and prednisolone 30 mg daily. He also suffered from hypertension and hypercholesterolemia, which were well controlled with amlodipine 10 mg and irbesartan hydrochlorothiazide, as well as atorvastatin, respectively.

On presentation, this man was started on bicalutamide, a GnRH antagonist, in addition to his regular leuprorelin acetate, however, he developed a suspected pneumonitis requiring immunosuppression with 40 mg prednisolone and plans to taper down as appropriate. Unfortunately, within 1 week he was admitted with a diverticular bleed in the setting of thrombocytopenia. Because of this complication and concerns regarding further use of bicalutamide, his therapy was changed to abiraterone in August of 2014 with a resultant drop in his PSA from 1750 &mu;g/L to 790 &mu;g/L. At this time, he remained on 7.5 mg daily prednisolone along with goserelin acetate every 3 months as an alternative GnRH agonist. He was also receiving denosumab every month at a dose of 120 mg. In December 2014, he was admitted for management of sepsis from a presumed respiratory source. He was commenced on empiric intravenous antibiotics with little improvement in his overall condition and referred to immunology at which point he was found to have hypogammaglobulinemia with a serum IgG of 4.7 g/L. His total peripheral blood B-cell count was reduced at 0.06 x 109/L (0.14-0.54). A detailed analysis of his peripheral blood B cells by flow cytometry with a chronic variable immunodeficiency (CVID) panel revealed a decreased proportion of memory B cells with a pattern consistent with Freiburg 1b.

He was commenced on IVIg replacement therapy, receiving 400 mg/kg every 4 weeks. A bone marrow examination performed because of a suspicion of macrophage activation syndrome did not support the latter, but did reveal extensive infiltration by prostate cancer cells and a marked reduction in trilineage hematopoiesis. Immunophenotyping showed a predominance of T cells over B cells with both lymphocyte populations appearing normal. His condition continued to deteriorate and the decision for supportive comfort measures was made by the treating team and his family.

A 73-year-old man with Gleason score 9 prostate cancer diagnosed in 2006 with locally advanced disease was started on leuprorelin acetate and bicalutamide with reasonable biochemical control. By late December 2012, his treatment was changed to degarelix, a GnRH receptor antagonist, with continuation of bicalutamide because of a progressive rise in PSA from 4.5 &mu;g/L to 10 &mu;g/L, however by 2013, the PSA had further risen to 36 &mu;g/L. He had a relevant past history of type II diabetes mellitus adequately controlled with oral hypoglycemics, hypertension, and previous episodes of pancreatitis. He also suffered from ischaemic heart disease requiring coronary artery vessel stenting in 2010, but which had remained well controlled from that time.

On presentation to medical oncology in December 2014, abiraterone was initiated, however, his medical management was complicated by recurrent episodes of fever for which no causative infective organism was identified. Further investigations revealed hypogammaglobulinemia with an IgG of 3.5 g/L, IgA of 0.58 g/L and IgM of 0.2 g/L, and he was subsequently referred for an immunological opinion. The total number of peripheral blood B cells (CD19) was low at 0.04 x 109/L (0.14-0.54). The CVID panel revealed decreased, but a normal fraction of memory B cells consistent with Freiburg 1b

and Paris MB indeterminate. 5 It was at this time that he was commenced on IVIg at a dose of 400 mg/kg every 4 weeks whilst continuing with abiraterone for ongoing control of the PSA. IgG improved to 6 g/L. He was managed with a tapering dose of prednisolone, stable at 10 mg daily along with abiraterone and had a continued PSA response from 1130 &mu;g/L to 820 &mu;g/L. In April 2015, he was admitted to hospital with a lower respiratory chest infection and sepsis requiring 10 days of intravenous antibiotics. The abiraterone was continued at this time and the PSA response was maintained with a further reduction to 780 &mu;g/L.

A 78-year-old man with Gleason score 9 prostate cancer was diagnosed in 2004 with PSA 12 &mu;g/L. At diagnosis he declined surgery or radiotherapy and commenced leuprorelin acetate. This was changed to goserelin acetate in 2012 because of drug availability and his disease remained under reasonable biochemical control. Between May and September of 2013, his PSA was noted to gradually rise from 9.5 &mu;g/L to 12.4 &mu;g/L with a further peak to 14.5 &mu;g/L by January of 2014, at which point his management was changed to degaralix. Unfortunately, this did not alter the disease behavior and his PSA increased further to 187 &mu;g/L by November of the same year prompting the addition of bicalutamide. Despite this, his PSA continued to increase to 191 &mu;g/L and staging investigations with CT confirmed multiple enlarged pelvic lymph nodes, as well as 2 small pulmonary nodules of uncertain significance. A whole body bone scan did not reveal bone metastases.

Relevant past medical history consisted of atrial fibrillation and stroke with residual left-arm weakness some 7 years previously. He had previously suffered a vertebral fracture in 2009 on a background of osteoporosis and also suffered from well- controlled hypertension. Medications included dabigatran, anti-reflux, and anti-hypertensive agents (diltiazem hydrochloride and perindopril erbumine with indapamide). He had been taking risedronate sodium, but was changed to denosumab for convenience and took iron supplements. At the time of review his disease was considered low volume so he was maintained on degarelix and bicalutamide; however, by February/March of 2015, his disease showed significant biochemical progression with PSA climbing to 2462 &mu;g/L. He was therefore changed to abiraterone with prednisolone and displayed an initial response with reduction in PSA to 1998 &mu;g/L. Unfortunately, he developed sepsis from an unknown source and was subsequently admitted for intravenous antibiotics. Given our previous experiences with abiraterone, serum immunoglobulins and CVID panels were ordered and he was found to be hypogammaglobulinemic with an IgG level of 4.2 g/L. His total B-cell count was reduced at 0.06 x 109/L (0.14-0.54). CVID panel revealed normal proportions of memory and switched memory B cells, but a high proportion of CD21-lo cells as a proportion of total B cells consistent with Freiburg 1b and Paris MB2 classifications.

Immunoglobulins IgG, A, and M were measured using a commercial immunoturbidometric assay (Architect c-system, Abbott Laboratories, Macquarie Park, NSW, Australia).

In addition, each patient had serum protein electrophoresis performed (SPIFE SPE, Helena Laboratories, Mt Waverley, Victoria, Australia ) with further immunofixation electrophoresis (SPIFE Immunofix, Helena laboratories) to diagnose or exclude any paraproteins.

Flow cytometric phenotyping was carried out as described by Warnatz and Schlesier.

Briefly, each patient underwent 2 analyses for peripheral blood lymphoid cells. The first panel consisted of total T cells (CD3), helper T cells (CD4), cytotoxic T cells (CD8), total B cells (CD19), and natural killer cells (CD16/56). The second panel known as the common variable immunodeficiency panel, CVID panel, because of its use in patients with the most common primary cause of hypogammaglobulinemia in adults, monitored B cells in more detail to identify the proportion of memory B cells, switched memory B cells, and transitional cells. The precise markers used are shown in the combined table of results. The combination of markers allows subdivision of patients into internationally defined subgroups. There are 2 main classification systems: Frieburg and Paris.

They have overlapping, but not identical definitions and in the absence of agreed international consensus, both are used in our laboratory. The rationale behind the use of this panel was that prostate cancer is a common malignancy and accordingly it was possible that CVID could develop spontaneously in these elderly men, and if this occurred, well-defined patterns of B cells should be seen.

Immunoglobulin measurements for patients are shown in

. All cases were IgG deficient. Case 2 who had mild IgA and IgM deficiency, normalized these 2 isotypes when on replacement with Intragam, which contains only IgG. IgG deficiency appears to predominate. Serum electrophoresis and immunofixation did not reveal any paraproteins in any patient. The B-cell analysis of patients are shown in

. These tests were performed to identify a consistent pattern, however no such pattern emerged.

Hypogammaglobulinemia is a cause for recurrent infections, but is generally not a feature of chemotherapeutic regimens for various solid malignancies. Infective risks associated with chemotherapy are more commonly associated with effects on innate immunity as evidenced by neutropenia, typically 7 to 10 days post therapy. However, with the advent of newer noncytotoxic treatment approaches, these more common associations are not standard.

The combination of immunoglobulin deficiency and advanced prostate cancer has been reported once before. The patient had a complete absence of circulating B cells and a combination of drug toxicities was considered the likely cause.

This and the 3 cases described here raise questions as to the possible basis of a relationship. The likelihood of all 3 patients developing CVID over a short time-frame seems most unlikely, however, it cannot be excluded. The lack of any specific consistent pattern of B-cell disturbance also argues against the development of CVID.

All patients received abiraterone, a new agent now being more widely used in the treatment of castrate-resistant metastatic prostate cancer that has shown promising results in terms of both progression-free survival (PFS) and overall survival (OS) and is now often considered a firstline therapy in elderly or more frail patients who would not otherwise be considered appropriate for conventional chemotherapeutic options. It is an inhibitor of 17 &alpha;-hydroxylase/C17, 20 lyase (CYP17a1), which is expressed in normal testicular and adrenal tissue as well as prostatic tumor tissue. CYP17a1 is a crucial enzyme in the conversion of pregnenolone-like steroids into the androgens, DHEA, and androstenedione. Therefore, this drug has the ability to effectively block both extragonodal and testicular androgen production, and diminish its levels in circulation. Because of its mechanism of action, abiraterone requires concomitant administration with prednisolone at a replacement dose of 10 mg a day to maintain basal corticosteroid levels without typical steroid related side effects.

Whilst abiraterone is associated with a wide variety of reported toxicities, the concurrent use of physiological replacement dose prednisolone should not contribute to increased infective risks nor should it give rise to hypogammaglobulinemia. A common feature reported here is the use of abiraterone, however, other factors which may account for the hypogammaglobulinemia could relate to impaired bone marrow function in the face of a very high-body burden of metastatic prostate cancer. This could include direct infiltration and replacement of antibody-producing cells or cytokine dysregulation and negative signalling to antibodyproducing cells. Case 1 had received pelvic irradiation and case 2 received prior azathioprine, both of which may have contributed. Furthermore, abiraterone may increase the survival of patients who have a greater disease burden than those who undergo standard treatments, and thus allow time for the development of this hypogammaglobulinemia.

In summary, we have described 3 cases of advanced prostate cancer patients receiving treatment with abiraterone who developed hypogammaglobulinemia and subsequent infections. These effects are unlikely to be a direct consequence of abiraterone, and may relate more to prolonged survival of patients with advanced disease due to newer therapeutic agents. In patients presenting with episodes of infection/sepsis, it may be worth assessing immunoglobulin levels as a possible cause.

Australian Institute of Health and Welfare 2016. Australian Cancer Incidence and Mortality (ACIM) books: prostate cancer. Canberra: AIHW. Accessed January 2016.

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Description of&nbsp;3 cases whereby significant septic complications occurred in the setting of abiraterone use that were associated with&nbsp;hypogammaglobulinemia.

Chandra Diwakarla, BSc (Hons), MBBS | Authors

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Hypogammaglobulinemia and Abiraterone Therapy for Metastatic Prostate Cancer