Thrombopoietin Receptor Agonists and Other Second-Line Therapies for Immune Thrombocytopenia: A Narrative Review With a Focus on Drug Access in Canada.

INTRODUCTION: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts and increased risk of bleeding. After corticosteroids with or without intravenous immune globulin (first-line treatment), second-line treatment options include rituximab, splenectomy, thrombopoietin receptor agonists (TPO-RAs), and fostamatinib. In Canada, the choice of second-line therapy is influenced by access to medications. The goals of this narrative review are to 1) summarize the evidence for the use of TPO-RAs and other second-line therapies in ITP and 2) highlight differences in public funding criteria for TPO-RAs across provinces and territories in Canada. METHODS: We conducted a literature review of second-line therapies for ITP. We solicited information on public funding programs for TPO-RAs in Canada from health care providers, pharmacists, and provincial ministries of health. RESULTS: Head-to-head trials involving TPO-RAs, rituximab, splenectomy, and fostamatinib are lacking. There is substantial evidence of effect for TPO-RAs in improving platelet count levels, health-related quality of life, bleeding, and fatigue from placebo-controlled trials and observational studies; however, access to TPO-RAs through provincial funding programs in Canada is variable. Splenectomy failure is a prerequisite for the funding of TPO-RAs in Ontario, Manitoba, and Saskatchewan, but not in Alberta or Quebec. Other provinces either do not have access to public funding or funding is provided on a case-by-case basis. DISCUSSION: TPO-RAs are effective second-line therapies for the treatment of ITP; however, access is variable across Canada, which results in health disparities and poor uptake of international treatment guidelines.

Molecular monitoring of therapeutic milestones and clinical outcomes in patients with chronic myeloid leukemia.

BACKGROUND: In the current study, the authors determined whether adhering to molecular monitoring guidelines in patients with chronic myeloid leukemia (CML) is associated with major molecular response (MMR) and assessed barriers to adherent monitoring. METHODS: Newly treated patients with CML from the Quebec province-wide CML registry from 2005 to 2016 were included. Timely polymerase chain reaction (tPCR) was defined as the molecular assessment of BCR-ABL1 at the 3-month, 12-month, and 18-month time points from the initiation of tyrosine kinase inhibitor (TKI) therapy. The cohort was analyzed as a nested case-control study. Cases with a first-ever MMR (BCR-ABL1 ≤0.1%, assessed at any time during follow-up) were matched to up to 5 controls by duration of TKI therapy, volume of patients with CML at the treatment center, year of cohort entry, and age. Odds ratios (ORs) for the performance of tPCR and MMR were adjusted for sex, comorbidities, type of TKI, and other important covariates. RESULTS: The cohort included 496 patients. Of 392 MMR events, 67.9% occurred before 18 months. The performance of tPCR was associated with a doubling of the MMR rate (OR, 2.23; 95% confidence interval [95% CI], 1.56-3.21) and was similar with 1 to 3 tPCRs performed (P = .67). Furthermore, tPCRs at 3 months (OR, 2.77; 95% CI, 1.81-4.23) and 12 months (OR, 3.00; 95% CI, 1.64-5.49) were associated with achieving early MMR, whereas tPCRs at 18 months were not (OR, 1.23; 95% CI, 0.80-1.89). Low-volume centers were found to have lower adherence to tPCR (OR, 0.60; 95% CI, 0.40-0.89). CONCLUSIONS: Timely molecular assessment at 3 months and 12 months appears to benefit patients with CML. Adherence to timely monitoring should be encouraged, especially in low-volume treatment centers.

A phase 2 trial of sunitinib in patients with progressive paraganglioma or pheochromocytoma: the SNIPP trial.

BACKGROUND: Pheochromocytoma (PCC) and paraganglioma (PGL) are uncommon neoplasms with high morbidity in advanced stages. Effective systemic treatments are limited. METHODS: A multisite phase 2 trial evaluated sunitinib in patients with progressive PCC/PGL. Patients received 50 mg orally for 4-6 weeks. RESULTS: Between May 2009 and May 2016, 25 patients were enroled. The median age was 50 years and 56% were male. Three patients (12%) received prior chemotherapy and 16 (64%) prior surgery. The DCR was 83% (95% CI: 61-95%) and median PFS 13.4 (95% CI: 5.3-24.6) months. Of 23 evaluable patients, 3 (13%) with germline mutations (SDHA, SDHB, RET) achieved a PR. The patient with mutated RET and MEN2A remains on treatment after 64 cycles. The median time on treatment was 12.4 (1-88.0) months. Grade 3 or 4 toxicities were as expected and manageable; fatigue (16%) and thrombocytopenia (16%) were most common. One patient with grade 3 hypertension and 2 with grade 3 cardiac events discontinued treatment. CONCLUSION: Although the primary endpoint of disease control was met, the overall response rate of sunitinib was low in unselected patients with progressive PCC/PGL. Patients with germline variants in RET or in the subunits of SDH may derive greatest benefit.

Salvage chemotherapy and autologous stem cell transplantation for transformed indolent lymphoma: a subset analysis of NCIC CTG LY12.

The treatment of transformed indolent lymphoma (TRIL) often includes salvage chemotherapy (SC) and autologous stem cell transplant (ASCT). NCIC CTG LY12 is a randomized phase 3 trial comparing gemcitabine, dexamethasone, and cisplatin (GDP) with dexamethasone, cytarabine, and cisplatin (DHAP) before ASCT. This analysis compares the results of SC and ASCT for TRIL with de novo diffuse large B-cell lymphoma (DLBCL). Six-hundred nineteen patients with relapsed/refractory aggressive non-Hodgkin lymphoma were randomized to GDP or DHAP; 87 patients (14%) had TRIL and 429 (69%) had DLBCL. The response rate to SC was 47% in TRIL and 45% in DL (P = .81). Transplantation rates were similar: TRIL 53% and DL 52% (P = 1.0). With a median follow-up of 53 months, 4 year overall survival was 39% for TRIL and 41% for DL (P = .78); 4 year event-free survival (EFS) was 27% for TRIL and 27% for DL (P = .83). Post-ASCT, 4-year EFS was 45% for TRIL and 46% for DL. Histology (TRIL or DL) was not a predictor of any outcome in multivariate models. Patients with relapsed or refractory TRIL and DLBCL have similar outcomes with SC and ASCT; this therapy should be considered the standard of care for patients with TRIL who have received prior systemic chemotherapy. NCIC CTG LY12 is registered at ClinicalTrials.gov as #NCT00078949.

Central Hypothyroidism is Frequent During Mitotane Therapy in Adrenocortical Cancer Patients: Prevalence and Timeline.

CONTEXT: Central hypothyroidism was described previously in mitotane-treated patients but data on its prevalence and time of occurrence are limited. OBJECTIVE: To better characterize thyroid hormone insufficiency in patients exposed to mitotane. METHODS: We reviewed medical records of patients from 2 academic centers in Montreal (Canada) and Toulouse (France) with exposure to mitotane therapy for adrenocortical cancer between 1995 and 2020. We analyzed the thyroid function parameters during and after treatment. RESULTS: In our cohort of 83 patients, 17 were excluded because of preexisting primary hypothyroidism or drug-induced hypothyroidism. During follow-up, 3/66 patients maintained a normal thyroid function and 63/66 developed central hypothyroidism. Among those 63 patients, 56 presented with an inappropriately normal or low TSH and 7 with a mildly elevated TSH. The onset of hypothyroidism was: <3 months in 33.3%, 3 to 6 months in 19.1%, 6 to 9 months in 14.3%, and 9 to 12 months in 9.5%. At least 14.3% of cases occurred after 12 months of exposure, and 6 patients had an undetermined time of occurrence. Over time, 27 patients stopped mitotane and partial (42.3%) or complete (23.1%) recovery from hypothyroidism was observed, mainly in the first 2 years after mitotane discontinuation. CONCLUSION: Mitotane therapy is frequently associated with new onset of central hypothyroidism with a prevalence of 95.5%. Most cases occurred in the first year of treatment. Partial or full recovery of thyroid function occurs in 65.4% of cases. This study supports the importance of systematic monitoring of TSH and free T4 levels during and following discontinuation of mitotane therapy.

Canadian real-world experience of asciminib treatment in heavily pre-treated chronic myeloid leukemia (CML) patients who failed multiple lines of tyrosine kinase inhibitor (TKI) therapy.

BACKGROUND: Asciminib is a novel drug specifically targeting ABL myristoyl pocket in the ABL1 protein. METHODS: Forty one patients with chronic myeloid leukemia treated with asciminib from 2018 to 2022 were reviewed and analyzed for the efficacy and tolerability of asciminib using real-world experience data. RESULTS: The median age was 60 years (range 17-90) with a past history of a cardiovascular event in 21 patients (51%). Patients were pretreated with a median of 3 previous tyrosine kinase inhibitors (range 1-5). After a median of 12 months of asciminib (range 3-41), major molecular response (MMR) rate was 39% (n = 11/28) and 42% (n = 5/12) at 6 and 12 months, respectively. Molecular response with 2 log reduction (MR2) was noted in 54% (n = 15/28) and 50% (n = 6/12) at 6 and 12 months. The cumulative incidence of MMR and MR2 was 46.3% and 66% at 12 months. Five patients discontinued asciminib due to treatment failure (n = 3) or thrombocytopenia (n = 2). There were no cardiovascular events. Out of 7 patients treated with high dose asciminib for T315I mutation, 5 patients achieved MMR or deeper response. The event-free survival was 63% at 12 months. CONCLUSION: This study confirmed clinical efficacy and tolerability of asciminib with real-world experience.

Postoperative Recurrences in Patients Operated for Pheochromocytomas and Paragangliomas: New Data Supporting Lifelong Surveillance.

At least 10% of pheochromocytomas (PHEOs) and paragangliomas (PGLs) (PPGLs) may recur after the initial surgery. Guidelines recommend annual screening for recurrence in non-metastatic tumors for at least 10 years after the initial surgical resection and lifelong screening in high-risk patients. However, recent data suggest that a shorter follow-up might be appropriate. We performed a retrospective analysis on patients with PPGLs who had local and/or metastatic recurrences between 1995 and 2020 in our center. Data were available for 39 cases of recurrence (69.2% female) including 20 PHEOs (51.3%) and 19 PGLs (48.7%) (13 head and neck (HNPGL) and 6 thoracoabdominal (TAPGL)). The overall average delay of recurrence was 116.6 months (14-584 months) or 9.7 years and the median was 71 months or 5.9 years. One-third of the cohort had a recurrence more than 10 years after the initial surgery (10-48.7 years). The average tumor size at initial diagnosis was 8.2 cm for PHEOs, 2.7 cm for HNPGLs, and 9.6 cm for TAPGLs. Interestingly, 17.6% of PHEOs were under 5 cm at the initial diagnosis. Metastatic recurrence was identified in 75% of PHEOs, 15.4% of HNPGLs, and 66.7% of TAPGLs. Finally, 12/23 (52.2%) patients with recurrence who underwent genetic testing carried a germline mutation. Overall, the safest option remains a lifelong follow-up.

Characterization of hyperlipidemia secondary to mitotane in adrenocortical carcinoma.

Background: This study examined the magnitude of changes and the time required to observe maximal changes in LDL-c, HDL-c, triglycerides (Tg) and non-HDL-c after the introduction of mitotane. Methods: Retrospective study of 45 patients with adrenocortical carcinoma who were treated at the Centre hospitalier de l'Université de Montréal. Clinical and biochemical data were collected, including lipid profiles before and during the first year of treatment with mitotane. Results: Among the 45 studied patients, 26 (58%) had a complete lipid profile before the introduction of mitotane and at least 1 lipid profile during the first year of treatment, and 19 patients (42%) had a lipid profile following initiation of the treatment. Among the 26 patients who had lipid profiles before and after the introduction of mitotane, the increase of LDL-c was 2.19 mmol/L (76%) (P< 0.0001), HDL-c was 0.54 mmol/L (35%) (P= 0.0002), Tg was 1.80 mmol/L (129%) (P< 0.0001) and non-HDL-c was 2.73 mmol/L (79%) (P< 0.0001). Between the first and the sixth month of mitotane treatment, peak values (n = 45) of LDL-c and non-HDL-c were reached in 42 patients (93%) and 37 patients (82%), respectively, whereas peak values of HDL-c were reached after 6 months of mitotane treatment in 29 patients (66%). The peak value of Tg was almost equal throughout the first year. The mean peak values of HDL-c, Tg and non-HDL-c showed significant associations with their respective mitotane concentrations (ß = 0.352, P= 0.03; ß = 0.406, P= 0.02 and ß = 0.339, P= 0.05). Conclusion: The introduction of mitotane produces a clinically significant elevation of lipid parameters (LDL-c, HDL-c, Tg and non-HDL-c) during the first year of treatment.

Adrenocortical cancer recurrence following initial transcutaneous biopsy: a rare demonstration of needle tract seeding.

Summary: Needle tract seeding is a potential, albeit rare, complication following transcutaneous biopsies, leading to the seeding of tumor cells along the path of the needle. Biopsies of adrenal masses are not routinely recommended and are only indicated, after exclusion of pheochromocytoma, when an adrenal metastasis of a primary extra-adrenal cancer is suspected or when pathological confirmation of inoperable adrenocortical cancer (ACC) may impact treatment. Despite guideline recommendations to avoid primary adrenal biopsy, very few needle tract seeding cases have been reported and none were in the context of an ACC. We report the occurrence of needle tract seeding in a patient following adrenal transcutaneous biopsy leading to ACC abdominal wall recurrence. Learning points: Needle tract seeding is a rare complication of transcutaneous biopsy. It may increase morbidity and impact overall survival. It has yet to be documented in adrenocortical carcinoma (ACC).Adrenal masses can be accurately evaluated for malignancy using a combination of conventional and metabolic imaging, such as CT and fluorodeoxyglucose-PET, obviating the need for biopsies.Adrenal mass biopsy is not indicated in ACC unless advanced ACC is diagnosed, and a pathological confirmation would impact management.

Small adrenal incidentaloma becoming an aggressive adrenocortical carcinoma in a patient carrying a germline APC variant.

PURPOSE: Recent guidelines on adrenal incidentalomas suggested in patients with an indeterminate adrenal mass and no significant hormone excess that follow up with a repeat noncontrast CT or MRI after 6-12 months may be an option. METHODS: We report the case of a 32-year-old woman who presented with a 2.9 × 1.9 cm left adrenal incidentaloma that was stable in size for 4 years. Ten years later the left adrenal mass was a stage IV adrenocortical carcinoma (ACC). RESULTS: In 2006, a 32-year-old French Canadian woman was referred to endocrinology for a left 2.9 × 1.9 cm incidentally discovered adrenal mass (31 HU). She had normal hormonal investigation. The patient was followed with adrenal imaging and hormonal investigation yearly for 4 years and the lesion stayed stable in size over the 4 years. Ten years later, in 2016, the patient presented with renal colic. Urological CT unexpectedly revealed that the left adrenal mass was now measuring 9 × 8.2 cm and 2 new hepatic lesions were found. Biochemical workup demonstrated hypercorticism and hyperandrogenemia: plasma cortisol after 1 mg overnight DST of 476 nmol/L and DHEA-S of 14.0 µmol/L (N 0.9-6.5). Twenty-four hour urine steroid profiling was consistent with an adrenocortical carcinoma (ACC) co-secreting cortisol, androgens and glucocorticoid precursors. The diagnosis of ACC with hepatic ACC metastases was confirmed at histology. Following genetic analysis, germline heterozygous variant of uncertain significance (VUS) was identified in the exon 16 of the APC gene (c.2414G > A, p.Arg805Gln). Immunohistochemical staining's of the ACC was positive for IGF-2 and cytoplasmic/nuclear ß-catenin staining. CONCLUSIONS: This case illustrates that (1) small adrenal incidentaloma stable in size may evolve to ACC and (2) better genetic characterization of these patients may eventually give clues on this unusual evolution.

Iron overload in myelodysplastic syndromes: a Canadian consensus guideline.

In December 2005, 11 Canadian hematologists met to develop an evidence-based clinical practice guideline that would address the diagnosis, monitoring, management, and rationale for the treatment of transfusional iron overload in patients with myelodysplastic syndromes (MDS). This Expert Panel consisted of hematologists from across Canada, each with an active practice in a major population centre or a rural area. Based on an extensive literature search and years of clinical experience, their mandate was to address common clinical practice questions, particularly why treat, whom to treat, when to initiate treatment, and how to treat iron overload in patients with MDS.

Evaluation of recurring cytogenetic abnormalities in the treatment of myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are clinically heterogeneous, but the presence of specific cytogenetic abnormalities can predict disease manifestations, provide a basis for prognosis, and direct treatment. Conventional cytogenetic analysis is instrumental in identifying chromosomal abnormalities in MDS and novel genetic methods may provide supplementary information. Treatment with lenalidomide was recently shown to be effective in MDS, particularly in those cases with del(5q), resulting in durable cytogenetic remission and hematological responses. In this paradigm, diagnosis of the del(5q) abnormality would be essential to predicting response to therapy.

Treatment of older patients with acute myeloid leukemia (AML): revised Canadian consensus guidelines.

The treatment of acute myeloid leukemia (AML) in older patients is undergoing rapid changes, with a number of important publications in the past five years. Because of this, a group of Canadian leukemia experts has produced an update to the Canadian Consensus Guidelines that were published in 2013, with several new agents recommended, subject to availability. Recent studies have supported the survival benefit of induction chemotherapy for patients under age 80, except those with major co-morbidities or those with adverse risk cytogenetics who are not candidates for allogeneic hematopoietic stem cell transplantation (HSCT). Midostaurin should be added to induction therapy for patients up to age 70 with a FLT3 mutation, and gemtuzumab ozogamicin for de novo AML up to age 70 with favorable or intermediate risk cytogenetics. Daunorubicin 60 mg/m2 is the recommended dose for 3+7 induction therapy. Acute promyelocytic leukemia should be treated with arsenic trioxide plus all-trans retinoic acid, regardless of age, with cytotoxic therapy added upfront only for those with initial white blood count > 10. HSCT may be considered for selected suitable patients up to age 70-75. Haploidentical donor transplants may be considered for older patients. For non-induction candidates, azacitidine is recommended for those with adverse risk cytogenetics, while either a hypomethylating agent (HMA) or low-dose cytarabine can be used for others. HMA may also be used for relapsed/refractory disease after chemotherapy. For patients with secondary AML, CPX-351 is recommended for fit patients age 60-75.

Rapid and Complete Remission of Metastatic Adrenocortical Carcinoma Persisting 10 Years After Treatment With Mitotane Monotherapy: Case Report and Review of the Literature.

Mitotane has been used for more than 5 decades as therapy for adrenocortical carcinoma (ACC). However its mechanism of action and the extent of tumor response remain incompletely understood. To date no cases of rapid and complete remission of metastatic ACC with mitotane monotherapy has been reported. A 52-year-old French Canadian man presented with metastatic disease 2 years following a right adrenalectomy for stage III nonsecreting ACC. He was started on mitotane which was well tolerated despite rapid escalation of the dose. The patient course was exceptional as he responded to mitotane monotherapy after only few months of treatment. Initiation of chemotherapy was not needed and he remained disease-free with good quality of life on low maintenance dose of mitotane during the following 10 years. A germline heterozygous TP53 exon 4 polymorphism c.215C>G (p. Pro72Arg) was found. Immunohistochemical stainings for IGF-2 and cytoplasmic ß-catenin were positive. Advanced ACC is an aggressive disease with poor prognosis and the current therapeutic options remain limited. These findings suggest that mitotane is a good option for the treatment of metastatic ACC and might result in rapid complete remission in selected patients.

Laboratory Investigation of Myeloproliferative Neoplasms (MPNs): Recommendations of the Canadian Mpn Group.

OBJECTIVES: To standardize diagnostic investigations for myeloproliferative neoplasms (MPNs) to increase homogeneity in patient care and to streamline diagnostic approaches in the most efficient and cost-effective manner. METHODS: The development of Canadian expert consensus recommendations for the diagnosis of MPNs began with a review of the following: clinical evidence, daily practice, existing treatment guidelines, and availability of diagnostic tools. Each group member was assigned a specific topic, which they discussed with the entire group during several consensus meetings. RESULTS: This document provides the Canadian MPN group's recommendations, proposed diagnostic algorithms, and background evidence upon which decisions were made. CONCLUSIONS: Standardization of diagnostic investigations will increase homogeneity in patient care and provide a foundation for future clinical research in this rapidly evolving therapeutic area. Streamlining diagnostic approaches in the most efficient and cost-effective manner will also result in significant cost saving for the health care system.