Tania Jain

Schnitzler syndrome: an under-diagnosed clinical entity

Schnitzler syndrome is considered to be a rare disorder characterized by a monoclonal IgM protein and chronic urticaria that is associated with considerable morbidity. We hypothesized that the syndrome may be under-recognized and patients may be deprived of highly effective therapy in the form of anakinra. We performed a retrospective search of the dysproteinemia database at Mayo Clinic as well as the medical records of all patients with chronic urticaria to determine the true incidence of the disease. We compared patients with the diagnosis of Schnitzler syndrome and those who met the criteria but in whom the syndrome was not recognized. Comparisons between groups were performed and survival curves determined. We identified 16 patients with diagnosed Schnitzler syndrome and an additional 46 patients who met diagnostic criteria. The monoclonal protein was IgMκ in 94% of patients. Therapy with anakinra in 4 patients led to rapid and complete resolution of symptoms. The median overall survival for this syndrome is over 12.8 years. Progression to lymphoma was only observed in 8% of patients; this is lower than previous reports. Schnitzler syndrome may be present in up to 1.5% of patients with a monoclonal IgM in their serum and likely under-recognized as a clinical syndrome.

Pegylated interferon alpha – 2a is clinically effective and tolerable in myeloproliferative neoplasm patients treated off clinical trial

Polycythemia vera, essential thrombocytosis, and myelofibrosis are chronic Philadelphia-negative myeloproliferative neoplasms that are characterized by clonal hematopoiesis, splenomegaly, risk of hemorrhagic and thrombotic sequelae, and profound symptom burden. We review the outcomes of 75 myeloproliferative neoplasm patients treated with pegylated interferon alpha 2a off study at an academic medical center. In the 56 treated polycythemia vera and essential thrombocytosis patients, a complete or partial response was obtained in 78.6% of patients per ELN/IWG-MRT revised criteria, with >80% of polycythemia vera patients becoming phlebotomy independent and 60% of essential thrombocytosis patients having platelet normalization with therapy. In the 19 treated myelofibrosis patients, stable disease was seen in 63.2% of patients. Vascular events occurred in 2/75 (2.6%) of treated patients while on therapy. Grade 3 toxicity was uncommon with leukopenia noted in 1 patient (1.3%). The most common adverse event overall was grade 1 fatigue in 18.7%. This retrospective single center analysis demonstrates pegylated interferon alpha 2a is active and well-tolerated therapy outside the support of a clinical trial. These results substantiate the previously reported efficacy of pegylated interferon alpha 2a in myeloproliferative neoplasms. Further prospective and randomized clinical trial data is required to better delineate pegylated interferon alpha 2as use in myeloproliferative disease, with emphasis placed on comprehensive molecular characterization, allelic burden quantification, and measurement of histologic response.

The development, safety and efficacy of pacritinib for the treatment of myelofibrosis

ABSTRACT Introduction: Dysregulation of janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has been described in myelofibrosis (MF). Currently, there is an unmet need for agents that have the benefit of JAK inhibition, yet also are safe and effective in patients with thrombocytopenia. Areas covered: We discuss the various preclinical and clinical studies describing pacritinib, a selective JAK2/FLT3 inhibitor. So far, it has shown promising results, without significant thrombocytopenia. A PubMed search, using keywords ‘pacritinib’, ‘SB 1518’ and ‘myelofibrosis’ was conducted. Published abstracts from recent national and international meetings were also reviewed for unpublished data. Expert commentary: Currently, pacritinib is on hold by Food and Drugs Administration. It would be imperative to understand if there is a treatment related toxicity that would limit its use. If a safe path is found for this agent, it could have a significant benefit in various settings, based on the data so far.

Phase II Trial of Nab‐paclitaxel in Patients with Relapsed or Refractory Multiple Myeloma

between 0.1% and 0.72%. There was a weak significant negative Spearman correlation between the percentage of these cells and age (r 5 20.232 P 5 0.022). We could not detect significant correlations between hematogones and the IPSS-R score, the number of aberrancies in the granulocytic lineage, or percentage of myeloid progenitors, but there were significant negative correlations with the number of monocytic aberrancies (r 5 20.256; P 5 0.012), the number of abnormalities of CD34 cells (r 5 20.206; P 5 0.044), and the total number of aberrancies detected (r 5 20.334; P 5 0.0008). In the univariate Cox regression, the percentage of B-cell precursors was a significant favorable prognostic factor for overall survival (B 5 26.220; P 5 0.011). In the Kaplan–Meier curve, patients with detectable B-cell precursors in BM had a significant better overall survival (log-rank test: P< 0.001) than patients with undetectable CD34/CD19/CD10 cells. After 5 years, 76.7% of the patients presenting BM hematogones at diagnosis were still alive, whereas this value dropped to 51.9% in patients without detectable B-cell precursors (Fig. 1). In a multivariate Cox regression model, the percentage of hematogones (B 5 25.061; P 50.006), of myeloid progenitors (B 5 0.191; P 50.02), and the IPSS-R score (B 5 0.714; P< 0.001) remained in the final model, thus demonstrating that the percentage of B-cell precursors is an independent favorable prognostic factor in MDS patients. In order to estimate the clinical importance of the variable “hematogones” in the model, we calculated the relative Akaike weights (w) for different models according to the Akaike information criteria. The relative weight for the prognostic model based only on IPSS-R was 0.0179 and raised to 0.112 in a model containing IPSS-R and the percentage of myeloid precursors. The weight was even higher in a model based on IPSS-R and the percentage of B-cell precursors (w 5 0.195), but the best model was achieved joining the variables “percentage of B-cell precursors,” “myeloid progenitors,” and the “IPSS-R score” (w 5 0.675). These data indicate that the percentage of hematogones in BM at diagnosis adds important prognostic information independent from already well-known prognostic features for overall survival in MDS patients. This is in keeping with similar results found in the setting of hematological recovery after allogeneic BM transplantation, where the absence of B-cell precursors in BM on day 130 was associated with a higher non-relapse mortality, a higher frequency of acute graft-versus-host disease and infections [6]. In normal individuals, there is a decrease of B-cell precursors, especially after the age 55 years, but these cells are even more decreased in patients with MDS compared to age-matched persons [5]. All these data indicate that the number of B-cell precursors in BM is not only a good marker of a preserved immune function but also for the integrity of the hemopoietic stem cell.

Intermittent BRAF Inhibition Can Achieve Prolonged Disease Control in BRAF Mutant Melanoma

BRAF V600E is the most common somatic mutation seen in patients with metastatic melanoma. BRAF inhibitors (BRAFi), along with MEK inhibitors (MEKi), have been shown to improve overall survival in these patients with a median time to resistance of 6-10 months. We describe a patient with an ongoing response of 48 months on intermittent BRAFi therapy. She was started on vemurafenib at initial diagnosis, which was discontinued after a total of 39 weeks of therapy, and achieved a complete response due to cumulative toxicity. Upon evidence of progression on serial imaging following 81 weeks of disease-free status, BRAFi was resumed with dabrafenib, along with trametinib. Complete response was seen with seven weeks of treatment. Therapy was discontinued again, due to side effects, with an intention to pursue intermittent therapy. Serial imaging, so far, has shown no progression or recurrence of disease after over a year (66 weeks and ongoing) since discontinuation of therapy. This case underscores the clinical feasibility of intermittent BRAFi therapy in patients while still achieving a prolonged response. Disease control of 48 months, to date, has been achieved using therapy only “as needed” and keeping toxicities to the minimum.

Systolic dysfunction associated with carfilzomib use in patients with multiple myeloma

Proteasome inhibition with carfilzomib (CFZ) has shown to be effective therapy in multiple myeloma (MM), with a response rate of around 87% and improved overall survival, in combination with lenalidomide and dexamethasone in patients with relapsed and refractory disease . Notably cardiac failure have been noted in 6–8% patients in these phase 3 trials, with 3–5% being grade 3 or higher. In a pooled analysis of 4 phase 2 clinical trials, cardiac failure was reported in approximately 7% patients and resulted in treatment discontinuation in 1.5% patients. The exact mechanisms behind cardiac dysfunction with CFZ are unknown. Some have postulated disturbance of endothelial nitric oxide synthase and nitric oxide. In a previous report from our group, the toxicity appeared to be the result of an endothelial effect given the cooccurrence with hypertension and elevation in creatinine. While cardiac toxicity has been reported with bortezomib, it appears to be more frequent with CFZ, possibly because CFZ is more potent and binds irreversibly to the β-subunit of the 20 S proteasome. This potency may also unmask potential protein metabolism consequences of proteasomal inhibition to the myocardium, a muscle in perpetual motion. Thus far, the predisposition, natural history, and reversibility of cardiac dysfunction are not well known. We share our experience of the clinical course of 12 patients who had worsening of cardiac function after initiation of CFZ. We identified 136 patients at Mayo Clinic in Arizona who received CFZ treatment for MM between July 2012 and June 2016. Twelve of those were known to develop worsening of cardiac function upon exposure to CFZ. A decrease in ejection fraction (EF), on transthoracic echocardiogram evaluation, by 5% resulting in EF< 55% with symptoms of congestive heart failure or drop in EF by 10% resulting in EF< 55% regardless of signs or symptoms, was defined as a cardiac event or cardiac dysfunction in this study. For patients who had a baseline EF less than 55%, any decline in EF was noted as the systolic dysfunction. We conducted a retrospective review of patients’ charts to obtain demographic and treatment-related information. Known risk factors for congestive heart failure such as gender, cigarette smoking, overweight, hypertension, history of cardiac disease, previous exposure to anthracyclines were evaluated. The study was approved by Institutional Review Board at Mayo Clinic Arizona.

Single dose versus multiple doses of rituximab for preemptive therapy of Epstein–Barr virus reactivation after hematopoietic cell transplantation

Abstract Epstein–Barr virus (EBV) reactivation is an unresolved medical issue after allogeneic hematopoietic stem cell transplantation (HSCT). Rituximab treatment is recommended for EBV reactivation after HSCT but the number of doses of rituximab to use is unclear. In this study, risk factors and outcomes of patients who needed 1 dose vs >1 doses of preemptive rituximab to clear EBV viremia were compared. A higher viral load was more likely to be associated with higher doses of rituximab. Patients whose EBV viremia cleared with 1 dose of rituximab were more likely to have a preceding reduction of immunosuppression. Overall survival (OS) in these 2 cohorts was not different (18.7 vs 26.6 months, respectively, p = .96). Since rituximab can have side effects and is fairly costly, a predictive model to determine the number of rituximab doses using viral load would be a useful and cost-effective manner to utilize rituximab for this indication.

Treatment with Bortezomib Based Therapy Followed by Autologous Stem Cell Transplantation Improves Outcomes in Light Chain Amyloidosis: A retrospective study

Background: The hematologic response is critical in patients with light chain amyloidosis because a good response is known to improve organ response and overall survival. We present a retrospective analysis to compare the hematologic and organ response in patients who received bortezomib‐based therapy before autologous stem cell transplantation (ASCT) versus those who received non–bortezomib‐based therapy before ASCT and those who underwent ASCT at diagnosis. Patients and Methods: Of a total of 63 patients who underwent ASCT for light chain amyloidosis, 34 received bortezomib‐based therapy before ASCT (Bor‐ASCT) and 29 did not receive bortezomib therapy (non‐Bor‐ASCT). A greater number of patients had involvement of ≥ 3 organs and cardiac involvement in the Bor‐ASCT group, suggesting a greater risk at baseline in the Bor‐ASCT group. Results: At 3, 6, and 12 months after ASCT, the hematologic response was better in the Bor‐ASCT group, with a statistically significance difference at 6 months (partial response or better in 82% vs. 20%; P = .002) and 12 months (partial response or better in 76% vs. 33%; P = .02). Organ responses (66% vs. 21%; P < .001) and median overall survival (not reached vs. 53 months; P = .001) were also greater in the Bor‐ASCT group. Conclusion: Our study has shown that bortezomib‐based therapy before ASCT improves the hematologic response, organ response and overall survival, potentially by decreasing the light chain load before ASCT. Micro‐Abstract We performed a retrospective study to compare the hematologic response, organ response, and overall survival in patients with light chain amyloidosis, receiving bortezomib‐based therapy before autologous stem cell transplantation (ASCT) versus non–bortezomib‐based therapy or no therapy before ASCT. In the present study, although the patients who received bortezomib before transplantation were at greater risk at baseline, we found significantly better outcomes in these patients.

Comparison of reduced intensity conditioning regimens used in patients undergoing hematopoietic stem cell transplantation for myelofibrosis

The aim of this study is to compare clinical outcomes of patients who underwent allogeneic stem cell transplantation (HCT) for myelofibrosis with reduced intensity conditioning (RIC) using either Busulfan Fludarabine (BuFlu), Fludarabine Bis-chlorethyl-nitroso-urea/ carmustine Melphalan (FBM) or Fludarabine Melphalan (FluMel) regimens. Sixty-one patients were identified who underwent HCT with one of these RIC regimens. Overall survival (OS) was not different in the 3 groups. However, 100% donor chimerism was seen in more frequently at day +30 and day +100 in patients who received FBM or FluMel than BuFlu, in both CD3 and CD33 fractions. For instance, 100% donor chimerism in CD33 fraction was present in 100% patients in FBM cohort, 90% in FluMel cohort while 44% in BuFlu cohort at day +100. Acute graft-versus host disease, grade 2–4 and grade 3–4, was not statistically different in the 3 groups (BuFlu 47 and 35%, FBM 68 and 27%, FluMel 68 and 46%; p = 0.31 and 0.45). Relapses and non-relapse mortality was also not statistically significantly different. Our study shows similar OS with these 3 RIC regimens in myelofibrosis; although donor chimerism at day +30 and day +100 was better in patients who received FBM and FluMel.

Rituximab maintenance therapy for mantle cell lymphoma: A systematic review and meta-analysis

Mantle cell lymphoma is characterized by relapse and progressive disease, despite initial response to chemoimmunotherapy. We conducted a systematic review and meta‐analysis to determine the efficacy of rituximab maintenance (RM) therapy in patients with mantle cell lymphoma. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials from database inception through November 1, 2017. Only full‐text articles were included. Prespecified data elements were extracted from each trial. Outcomes of interest included progression‐free survival (PFS) and overall survival (OS). The overall effect was pooled using the Der Simonian‐Laird random effects model. Three randomized controlled trials and four observational studies met our inclusion criteria and were identified in the analyses. Six studies compared RM therapy to observation, and one compared RM therapy to interferon alfa. Meta‐analysis evaluating outcomes of patients treated after ASCT revealed that RM improved for both PFS (HR = 0.33, 95% CI = 0.23‐0.49) and OS (HR of death = 0.35, 95% CI = 0.17‐0.69). A second meta‐analysis of studies evaluating outcomes of patients who are ASCT‐ineligible treated with anthracycline‐based induction therapy revealed that RM improved PFS (HR = 0.38, 95% CI = 0.25‐0.58). There is a paucity of data on the role of RM in ASCT‐ineligible patients and those with relapsed disease. Overall, RM therapy appears to improve PFS and OS in previously untreated patients with mantle cell lymphoma who undergo induction chemoimmunotherapy followed by ASCT.