Confirmed Thyroiditis or thyroid storm of some sort! TSH 0.01 and Free T4 3.5 ng/dl

Incidence of Thyroid-Related Adverse Events in Melanoma Patients Treated with Pembrolizumab. de Filette, Jansen, Schreuer, et al. J Clin Endocrinol Metab. 2016 Aug 29.

Okay – up next articles related to immunosuppressive therapies while on immunotherapy…….

Immune checkpoint blockade is associated with endocrine-related adverse events. Thyroid dysfunction during pembrolizumab therapy, an anti-programmed cell death 1 receptor (PD-1) monoclonal antibody (mAb), remains to be fully characterized. Thyroid function was monitored prospectively in melanoma patients who initiated pembrolizumab within an expanded access program at a referral oncology center. 18Fluorodeoxyglucose uptake on positron emission tomography/computed tomography (18FDG-PET/CT) was reviewed in cases compatible with inflammatory thyroiditis. 99 patients with advanced melanoma (aged 26.3-93.6 years; 63.6% females) who received at least 1 administration of pembrolizumab. 18 adverse events of thyroid dysfunction were observed in 17 patients. Thyrotoxicosis occurred in 12 patients of which 9 evolved to hypothyroidism. Isolated hypothyroidism was present in 6 patients. Levothyroxine therapy was required in 10 of 15 hypothyroid patients. Thyroid autoantibodies were elevated during thyroid dysfunction in 4 of 10 cases. Diffuse increased 18FDG uptake by the thyroid gland was observed in all 7 thyrotoxic patients who progressed to hypothyroidism. Thyroid dysfunction is common in melanoma patients treated with pembrolizumab. Hypothyroidism and thyrotoxicosis related to inflammatory thyroiditis are the most frequent presentations. Serial measurements of thyroid function tests are indicated during anti-PD-1 mAb therapy. Thyrotoxicosis compatible with inflammatory thyroiditis was associated with diffuse increased 18FDG uptake by the thyroid gland. The prospective role of thyroid autoantibodies should be further investigated together with the histopathological correlates.

Nivolumab-induced thyroid dysfunction. Tanaka, Fujisaw, Maruyama, et al. Jpn J Clin Oncol. 2016 Mar 23.

Nivolumab (ONO-4538) is an anti-programmed death-1 specific monoclonal antibody, which has become a standard treatment for metastatic malignant melanoma. Nivolumab induces autoimmune adverse events, defined as immune-related adverse events. Herein, we report a case of nivolumab-induced thyroid dysfunction in the clinical setting. Fourteen patients were treated with nivolumab at our institute, of which three developed thyroid dysfunction, an incidence higher than previously reported in the initial clinical trials. Interestingly, one patient achieved complete remission; suggesting that in some patients, the occurrence of immune-related adverse events, including thyroid dysfunction, might reflect the drug’s antitumour efficacy. No patient died or discontinued nivolumab treatment owing to thyroid dysfunction. Although thyroid dysfunction first appeared to be asymptomatic, two of the three patients developed symptoms related to hypothyroidism soon after, requiring hormone replacement therapy. Another patient developed hyperthyroidism that was initially asymptomatic; the patient subsequently developed myalgia with fever >39.5°C after two additional courses of nivolumab. Treatment with nivolumab was therefore discontinued, and treatment with prednisolone was initiated. Symptoms resolved within a few days, and thyroid function normalized. Thyroid dysfunction is sometimes difficult to diagnose because its symptoms similar to those of many other diseases. In addition, thyroid-related immune-related adverse events may present with unique symptoms such as myalgia with high fever, abruptly worsening patients’ quality of life. Consequently, thyroid dysfunction should be considered as a possible immune-related adverse event. Thus, it is important to test for thyroid dysfunction at baseline and before the administration of each nivolumab dose if possible.

Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism. Win, Thein, Qdaisat, and Yeung. Am J Emerg Med. 2017 Feb 27.

Ipilimumab (a monoclonal antibody against CTLA-4) and nivolumab (a humanized antibody against PD-1) target these immune checkpoint pathways and are used for treatment of melanoma and an increasing number of other cancers. However, they may cause immune-related adverse effects (IRAEs). Although many endocrinopathies are known to be IRAEs, primary hypoparathyroidism with severe hypocalcemia has never been reported. This is the first case of hypoparathyroidism as an IRAE presenting to an Emergency Department with acute hypocalcemia. A 73-year-old man with metastatic melanoma presented to the Emergency Department for the chief complaints of imbalance, general muscle weakness, abdominal pain and tingling in extremities. He had wide spread metastasis, and begun immunotherapy with concurrent ipilimumab and nivolumab 1.5months ago. At presentation, he had ataxia, paresthesia in the hands and feet, and abdominal cramping. Magnetic resonance imaging of the brain was unremarkable. He was found to be hypocalcemic with undetectable plasma parathyroid hormone. He was admitted for treatment of symptomatic hypocalcemia and was diagnosed with primary hypoparathyroidism. Shortly afterwards, he had thyrotoxicosis manifesting as tachycardia and anxiety, followed by development of primary hypothyroidism. At 4months after the Emergency Department visit, his parathyroid function and thyroid function had not recovered, and required continued thyroid hormone replacement and calcium and vitamin D treatment for hypocalcemia. Primary hypoparathyroidism caused by ipilimumab and nivolumab may acute manifest with severe symptomatic hypocalcemia. Emergency care providers should be aware of hypoparathyroidism as a new IRAE in this new era of immuno-oncology.

Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Ryder, Wolchok, et al. Edocr Relat Cancer. 2014 March 7.

“Novel immune checkpoint blockade with [ipi], an antibody blocking the cytotoxic T-lymphocyte antigen 4 is revolutionizing cancer therapy. However, [ipi] induces symptomatic and sometimes severe, endocrine immune-related adverse events that are inconsistently recognized and reported.” In a retrospective study these folks looked at 256 records of patients receiving ipi in clinical trials between 2007 and 2013. They looked at their hormone related labs, X-ray results, and clinical histories. After ipi, they found that the patients demonstrated an 8% incidence of hypophysitis, 6% dealt with hypothyroidism/thyroiditis, and primary adrenal dysfunction was rare. When Nivo and ipi
were given together, there was a 22% incidence of either thyroiditis or hypothyroidism, and a 9% incidence of hypophysitis. “Symptomatic relief, in particular, for hypophysitis, was achieved in all patients with hormone replacement, although endogenous hormone secretion was rarely recovered.” “Prompt initiation with hormone replacement reverses symptoms.”

From my own nivo only study:
Toxicities: 481 grade 1-5 adverse events were reported with 286 attributed to treatment. AE distribution was similar across cohorts (#1 = 81, #2 = 104, and #3 = 101). Most common AE’s were vaccine injection site reaction (discomfort, granuloma, and/or reactive lymphadenopathy – 94% of patients), fatigue (82%), rash (55%), pruritis (42%), nausea (42%), arthralgias (42%), diarrhea (36%), headache (36%). 5 drug related grade 3-5 AE’s were noted: hypokalemia (1 in cohort 2), rash (1 in cohort 1), enteritis (1 in cohort 3), and colitis (2 in cohorts 2 and 3). The colitis patients responded to high-dose steroids and supportive care. The patient with the grade 3 rash was re-challenged with the study drug after recovery; there was no recurrence of serious rash. Other immune-related events = grade 2 hypophysitis (2) leading to adrenal insufficiency in both patients, grade 2 thyroiditis (7) leading to primary hypothyroidism, and grade 1 pneumonitis (1) without clinical sequelae. Adrenal insufficiency and hypothyroidism were successfully managed with hormone replacement.

This excellent PDF I shared previously on how to treat side effects from immunotherapy with a algorithm for endocrine side effects in particular: http://theoncologist.alphamedpress.org/content/early/2016/07/08/theoncologist.2016-0055.full.pdf

Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center. Horvat, Adel, Dang, et al. J Clin Oncol. 2015 Aug 17.

Ipilimumab is a standard treatment for metastatic melanoma, but immune-related adverse events (irAEs) are common and can be severe. We reviewed our large, contemporary experience with ipilimumab treatment outside of clinical trials to determine the frequency of use of systemic corticosteroid or anti-tumor necrosis factor α (anti-TNFα) therapy and the effect of these therapies on overall survival (OS) and time to treatment failure (TTF).

We reviewed retrospectively the medical records of patients with melanoma who had received treatment between April 2011 and July 2013 with ipilimumab at the standard dose of 3 mg/kg. We collected data on patient demographics, previous and subsequent treatments, number of ipilimumab doses, irAEs and how they were treated, and overall survival.

Of the 298 patients, 254 (85%) experienced an irAE of any grade. Fifty-six patients (19%) discontinued therapy because of an irAE, most commonly diarrhea. Overall, 103 patients (35%) required systemic corticosteroid treatment for an irAE; 29 (10%) also required anti-TNFα therapy. Defining TTF as either starting a new treatment or death, estimated median TTF was 5.7 months. Twelve percent of patients experienced long-term disease control without receiving additional antimelanoma therapy. OS and TTF were not affected by the occurrence of irAEs or the need for systemic corticosteroids.

IrAEs are common in patients treated with ipilimumab. In our experience, approximately one-third of ipilimumab-treated patients required systemic corticosteroids, and almost one-third of those required further immune suppression with anti-TNFα therapy. Practitioners and patients should be prepared to treat irAEs and should understand that such treatment does not affect OS or TTF.

Correlation between toxicity and outcome in melanoma patients treated with ipilimumab plus nivoumab (ipi/nivo). Cohen, Jilaveanu…Sznol, et al. Society for Melanoma Research 2016 Congress. Published 29 January 2017.

Immune checkpoint inhibitors have become the standard of care for treatment of metastatic melanoma. However immune-related adverse events (irAEs) remain a serious concern. We report our experience investigating the potential correlation between degree of toxicity and progression-free survival (PFS). 74 pts were treated with the combination of ipi/nivo as part of the phase I trial, [NCT01024231], an expanded access protocol [NCT02186249] or with commercially available drugs from Dec. 2009 to Oct. 2015. irAEs were graded according to the CTCAE v4.0 and steroid use was studied as a surrogate for overall toxicity. 69 (93%) pts experienced an irAE of any grade. 39 pts (53%) had a grade 3 irAE and 4 (5%) had a grade 4 irAE. Pts often experienced greater than1 irAE. Females tended to get more toxicities than males. The median PFS in the patient population was 9 months (range 0–65). The median OS was 16 months (range 3–65). The objective response rate was 55%. 70 pts survived greater than 6 months. There was a statistically significant difference in the PFS in pts who experienced no irAEs when compared with those who had any irAEs. Similar findings were seen in the analysis of OS. PFS and OS were also stratified by length of time on steroids. Any steroid requirement at all was associated with a reduced risk of disease progression but the number of days on steroids above the median (23 days) corresponded with an increased risk of progression. Pts treated with the combination of ipi/nivo who received steroids to treat autoimmune toxicity had improved outcomes when compared with those pts who received no steroids, suggesting that pts who have some irAEs from immunotherapy may have improved outcomes. However, a fine balance between autoimmunity and anti-tumor response may be necessary for optimal long-term outcomes. THEN…….this part is my take: Here, of 74 patients treated with ipi/nivo, 93% had some level of side effects and 39 (once again, more than 50%) experienced Grade 3/4 side effects. PFS was 9 months. OS was 16 months. Objective response rate was 55%. 70 of the 74 lived more than 6 months. OKAY…but to the point of the current question: “There was a statistically significant difference between the PFS in patients” with NO side effects when compared to those who had ANY. This was true of overall survival as well. Furthermore, “Any steroid requirement at all was associated with a reduced risk of disease progression.” However, the authors go on to employ a caveat, noting that if steroid use was prolonged (beyond the average 23 days) there was a corresponding “increased risk of progression.” Now…what is unclear about that statement to me is this: Did prolonged steroid use actually account for the increased risk of progression? OR… Were these patients so badly affected by their adverse reactions to the treatment that they were unable to continue therapy and in the absence of treatment progressed? Especially if side effects occurred early and the amount of immunotherapy they had received was minimal????

Then there is this entire post (article and my yelling included) – here’s the link where it might be easier to read: http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2017/03/patients-with-preexisting-immune.html

SUNDAY, MARCH 5, 2017 Patients with preexisting immune disease, melanoma, and treatment with Anti-PD-1? Yes, this can be done. Yes, autoimmune flares should be treated with immunosuppressive therapy while on immunotherapy. And YES!!!! These patients can still attain a response!

Back when the world was young (2010 or so) and ipi (in other words, immunotherapy period) was finally producing positive responses for folks with melanoma, we simultaneously learned of the negative effects that could be wrought on the poor patient’s immune system and really feared what could possibly happen if you were treated with immunotherapy when you KNEW that you already had an existing autoimmune disease process like asthma, colitis, or arthritis. The solution by pharma and researchers? Exclusion from treatment!!! By 2014, with this still unsolved conundrum hanging in the air, we certainly didn’t know what to do with folks who developed immune related side effects to ipi, but still needed treatment for melanoma. Could they be treated with the two newer immunotherapy drugs, anti-PD-1 products Nivo (Opdivo) or Pembro (Keytruda)? No! Exclusion from treatment remained the norm…as you can see in this post!! (Yes, children. Folks talked pretty funny back then, calling Keytruda, first MK-3475, then Lambrolizumab, then Pembrolizumab! Crazy things happen when the world is new!!)

Anyhow – here’s the link:

Program for MK-3475 in Participants With Metastatic Melanoma Who Have Failed Standard of Care Therapy Including Ipilimumab (MK-3475-030) which says in part, with my response:
Exclusions include – “history of life-threatening or severe immune-related adverse event” on prior immunotherapy. Who decides? Is an admission for colitis on ipi, though now recovered, considered a “severe immune-related adverse event”? Is ipi induced hypothyroidism?

As things moved along…there was this: April 2016: Anti-PD1 success in melanoma despite prexisting autoimmune disease, a case report

And this from ASCO (See the first abstract): ASCO 2016 – Three anti-PD-1 reports

Now, there’s this:

Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity. Gutzmer, Koop, Meier, et al. Eur J Cancer. 2017 Feb 16.

Programmed cell death protein 1 (PD-1) inhibitors are a common treatment strategy for metastatic melanoma and other tumour entities. Clinical trials usually exclude patients with preexisting autoimmune diseases, thus experience with PD-1 inhibitor (PD-1i) in this patient population is limited.
Metastatic melanoma patients with preexisting autoimmune disorders or previous ipilimumab-triggered immune-related adverse events (irAE) undergoing treatment with PD-1i from seven German skin cancer centres were evaluated retrospectively with regard to flare of the preexisting autoimmunity and development of new, not preexisting irAE as well as response to PD-1i therapy.
In total, 41 patients had either preexisting autoimmunity (n=19, group A, including two patients with additional ipilimumab-triggered autoimmune colitis) or ipilimumab-triggered irAE (n=22, group B). At PD-1i therapy initiation, six patients in group A and two patients in group B required immunosuppressive therapy. In group A, a flare of preexisting autoimmune disorders was seen in 42% of patients, new irAE in 16%. In group B, 4.5% of patients showed a flare of ipilimumab-triggered irAE and 23% new irAE. All flares of preexisting autoimmune disorders or irAE were managed by immunosuppressive and/or symptomatic therapy and did not require termination of PD-1i therapy. tumour responses (32% in group A and 45% in group B) were unrelated to occurrence of autoimmunity.
While preexisting autoimmunity commonly showed a flare during PD-1i therapy, a flare of ipilimumab-triggered irAE was rare. Response rates were above 30% and unrelated to irAE. PD-1i therapy can be considered in patients with autoimmune disorders depending on severity and activity of autoimmunity.

So….while caution and careful monitoring is certainly warranted…these peeps with an inherent pre-existing autoimmune process or one gained from having taken ipi….were successfully managed with “immunosuppressive therapy”, “did not require termination of anti-PD-1 therapy”, AND gained responses at a rate of 32-45%!!!!!!!!!!!!!!

ONE MORE TIME! Folks with immune disease took anti-PD-1, took prednisone or other immunosuppressive treatment to manage flares, did NOT have to stop anti-PD-1 therapy, and many DID gain a response!

Could all you oncologists out there read and repeat?? Folks with auto-immune conditions CAN take immunotherapy with careful monitoring. Auto-immune flares SHOULD be treated with immunosuppressive therapy while on immunotherapy. AND these patients can STILL…..GAIN A RESPONSE!

And in case that still isn’t clear enough… What happens to folks with recurrent Stage IV melanoma who aren’t effectively treated???? There ain’t no Stage V people!
Okay, I’ll quit yelling. For now. – c

This post has a link to an inservice on the topic by Postow and Wolchok.
Here’s the link and copy is below: http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2016/12/one-more-time-immunosuppressive-therapy.html
One more time: Immunosuppressive therapy to manage side effects to immunotherapy does NOT affect response! New report.

I get asked repeatedly…and so many docs seem to have fallen behind the learning curve on this:

Do steroids and other drugs that suppress the immune response, when NEEDED for immune related side effects caused by immunotherapy, also diminish the critical response required to get rid of melanoma?

The short answer is no!!! Here’s info from two melanoma experts, published October 26, 2016 ~
Toxicities associated with checkpoint inhibitor immunotherapy – From UpToDate, with Postow and Wolchok
In the report it states: “The need for immunosuppressive therapy to manage irAEs does not appear to affect the response to checkpoint inhibition.”

And because nothing in melanoma can be simple….there is this:from 2018 ~ Do glucocorticoids or dexamethasone reduce the effectiveness of immunotherapy in melanoma??? https://chaoticallypreciselifeloveandmelanoma.blogspot.com/2018/07/do-glucocorticoids-or-dexamethasone.html

And….I don’t have any absolute answer to either of your questions. But here are my thoughts:

First and foremost, your cousin needs to see an endocrinologist. Oncs well versed in immunotherapy handle some side effects, even endocrine related ones, very well but this sounds pretty extreme and I think he would benefit from an endo as soon as possible, but perhaps that has already happened.

I feel like this is the first wave of his thyroid system burning out due to severe inflammation and soon (relatively) he will have hypothyroidism. I could be wrong about that, but that is my best guess. Along with that, once there is no thyroid function, as you know he would be maintained on oral supplementation of the needed hormone and I would see no impediment to taking ipi, ipi/nivo, or nivo as the damage to that gland is done and can neither be undone nor could his current circumstance recur.

I think the data is pretty clear that treating patients with immunosuppressive drugs (from steroids to things like infliximab, etc.) while on immunotherapy or while peeps are on a break from treatment is….
1. REQUIRED to maintain life….in some instances
2. Absolutely needed to maintain quality of life in lots of cases
3. Necessary in order to tamp down signs and symptoms so that patients can return to immunotherapy in order to beat melanoma!!!
4. Does NOT diminish positive effects of said immunotherapy in many studies
5. But as always with melanoma and its treatments – we are still learning.

Also in thinking about whether, given his current signs and symptoms, could your cousin return to immunotherapy? I think once the thyroid levels are under control, the answer is yes. There are more and more studies specific to folks who developed immune reactions while on immunotherapy or folks with pre-existing immune conditions who go on to tolerate immunotherapy well despite those situations – albeit with close monitoring and even with simultaneous steroids as needed – and YES – they gain positive responses!!!

And…lots of peeps on this forum and many in the literature took one form of immunotherapy or the other and gained little or no response, but with a change to or an addition of another immunotherapy – went on to do very well.

You are a wonder, Jackie. You have often made me think of my dear sister Ruthie in many ways. She is a nurse now….but wasn’t when I started on my melanoma crazy. Years later she confessed to sitting with a medical dictionary as she tried to make sense of the things I told her or sent her regarding my diagnosis or treatment. Without the support of many, but her and my B in particular, I would not be here. Period. You are doing no small thing for your cousin. Bless you always. Les

After one nivo treatment my TSH went from 4 to .01 and my free T4 doubled. Doc put me on steroids. Next month my TSH was 60. Decided to drop out of the trial.
That was a year ago and I have been on a full replacement dose of levothyroxine ever since.