Impact of second primary malignancy post-autologous transplantation on outcomes of multiple myeloma: a CIBMTR analysis.

The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P < .001 and HR 5.01, P < .001, respectively) and OS (HR 3.85, P < .001 and HR 8.13, P < .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT.

Outcomes of Patients with Thrombocytopenia Evaluated at Hematology Subspecialty Clinics.

BACKGROUND: Thrombocytopenia is a frequently encountered laboratory abnormality and a common reason for hematology referrals. Workup for thrombocytopenia is not standardized and frequently does not follow an evidence-based algorithm. We conducted a systematic analysis to evaluate the laboratory testing and outcomes of patients evaluated for thrombocytopenia at hematology clinics in a tertiary referral center between 2013 and 2016. PATIENT AND METHODS: We performed a comprehensive chart review for patients evaluated for thrombocytopenia during the study period. Patients were followed for 1 year from the initial hematology evaluation and assessed for the development of a hematologic malignancy, rheumatologic, or infectious diseases among other clinical outcomes. RESULTS: We evaluated 472 patients with a median (range) age of 61 (17-94) years. The majority (63.8%) had mild thrombocytopenia. Within 1 year of follow-up, 14 patients (3.0%) were diagnosed with a hematologic malignancy. A higher likelihood of developing a hematologic malignancy was noted in patients with concurrent leukopenia (hazard ratio [HR] 9.97, 95% confidence interval [CI] 3.28-30.32, p < .01) and increasing age (HR per 10-year deciles 1.52, 95% CI 1.03-2.25, p = .03). In patients with asymptomatic isolated mild thrombocytopenia, laboratory testing did not reveal any significant positive findings and patients did not receive any new major diagnosis during the follow-up period. CONCLUSION: Our findings provide basis and call for development of an evidence-based algorithmic approach for evaluation of patients with thrombocytopenia, testing, and referrals. It also supports a conservative approach mainly driven by physical exam signs, symptoms, and other laboratory findings for patients with isolated mild thrombocytopenia.

Delayed kidney transplantation after HLA-haploidentical hematopoietic cell transplantation in a young woman with myelodysplastic syndrome with renal failure.

Patients with end-stage renal disease (ESRD) are often excluded from potentially curative allogeneic hematopoietic cell transplantation (alloHCT). Our institution pioneered simultaneous living donor kidney transplantation in patients undergoing alloHCT from the same donor for hematologic malignancies. Herein, we present the case of a 31-year-old woman diagnosed with myelodysplastic syndrome who developed ESRD during cytoreductive induction therapy. She achieved disease control, then successfully underwent a human leukocyte antigen (HLA)-haploidentical alloHCT while on hemodialysis. After rapidly tapering off graft-versus-host disease prophylaxis, fourteen months from her alloHCT she received a kidney transplant from her same haploidentical sibling donor, which obviated the need for further systemic immunosuppression.

Comparative study of therapy-related and de novo adult b-cell acute lymphoblastic leukaemia.

We report a comparative analysis of patients with therapy-related acute lymphoblastic leukaemia (tr-ALL) vs de novo ALL. We identified 331 patients with B-ALL; 69 (21%) were classified as tr-ALL. The most common prior malignancies were breast (23·2%) and plasma cell disorders (20·3%). Patients with tr-ALL were older (median 63·2 vs. 46·2 years, P < 0.001), more often female (66·7% vs. 43·5%, P < 0·001), and more likely to have hypodiploid cytogenetics (18·8% vs. 5·0%, P < 0·001). In multivariable analysis, patients with tr-ALL were less likely to achieve complete remission [odds ratio (OR) = 0·16, P < 0·001] and more likely to be minimal residual disease-positive (OR = 4·86, P = 0·01) but had similar OS after diagnosis and allo-haematopoietic cell transplantation.

Maintenance therapy after second autologous hematopoietic cell transplantation for multiple myeloma. A CIBMTR analysis.

The role of maintenance therapy after high-dose chemotherapy and first autologous transplantation in multiple myeloma (MM) is well established. We explored the effect of maintenance therapy on outcomes after salvage second autologous hematopoietic cell transplant (AHCT2) using the Center for International Blood and Marrow Transplant Research registry. Outcomes of interest included non-relapse mortality (NRM), relapse/progression (REL), progression-free and overall survival (PFS, OS). Of 522 patients who underwent AHCT2 between 2010 and 2018, 342 received maintenance therapy and 180 did not. Maintenance regimens included lenalidomide (42%), pomalidomide (13%), and bortezomib (13%). Median follow up was 58 months in the maintenance group and 61.5 months in the no-maintenance group. Univariate analysis showed superior outcomes at 5 years in maintenance compared to the no-maintenance group: NRM 2 (0.7-3.9)% vs 9.9 (5.9-14.9)%, (p < 0.01), REL 70.2 (64.4-75.8)% vs 80.3 (73.6-86.3)% (p < 0.01), PFS 27.8 (22.4-33.5)% vs. 9.8 (5.5-15.2)% (p < 0.01), and OS 54 (47.5-60.5)% vs 30.9 (23.2-39.2)% (p < 0.01), respectively. Use of maintenance therapy retained its association with improved outcomes in multivariate analysis. There was no difference in second cancers in the two groups (p = 0.39). We conclude that maintenance after AHCT2 is associated with improved 5-year outcomes.

Induction Therapy Prior to Surgical Resection for Patients Presenting with Locally Advanced Esthesioneuroblastoma.

Esthesioneuroblastoma (ENB) is a rare olfactory malignancy that can present with locally advanced disease. At our institution, patients with ENB in whom the treating surgeon believes that a margin-negative resection is initially not achievable are selected to undergo induction with chemotherapy with or without radiotherapy prior to surgery. In a retrospective review of 61 patient records, we identified six patients (10%) treated with this approach. Five of six patients (83%) went on to definitive surgery. Prior to surgery, three of five patients (60%) had a partial response after induction therapy, whereas two of five (40%) had stable disease. Microscopically margin-negative resection was achieved in four of five (80%) of the patients who went on to surgery, while one patient had negative margins on frozen section but microscopically positive margins on permanent section. Three of five patients (60%) recurred after surgery; two of these patients died with recurrent/metastatic ENB. In summary, induction therapy may facilitate margin-negative resection in locally advanced ENB. Given the apparent sensitivity of ENB to chemotherapy and radiotherapy, future prospective studies should investigate the optimal multidisciplinary approach to improve long-term survival in this rare disease.

Molecular-Driven Therapy in Advanced Thyroid Cancer.

OPINION STATEMENT: With a growing understanding of the biologic drivers of different thyroid cancers, there is an ongoing revolution in the treatment of aggressive and advanced disease variants. This includes matching patients with specific point mutations or gene fusions to targeted therapies (e.g., selective RET inhibitors), delineating patients who are likely to respond to immune checkpoint inhibition (i.e., PD-L1-positive tumors) and even priming responses to traditional therapies such as radioactive iodine (via concomitant MAPK pathway inhibition). There is also a growing role for genomics in the prognostication of thyroid tumors to aid the adjudication of appropriate treatments. Taking stock of the current state of the field, recent successes should be celebrated, but there still remains a long road ahead to improve outcomes for patients, particularly for radioactive-iodine refractory differentiated thyroid cancer and anaplastic thyroid cancer. In this review, we summarize findings from recent clinical trials and highlight promising preclinical data supporting molecular-driven therapy in advanced thyroid cancer. Ultimately, enrollment in clinical trials remains paramount to the advancement of thyroid cancer care.

Donor cell-derived chronic myelomonocytic leukemia presenting after allogeneic hematopoietic cell transplantation for T-cell acute lymphoblastic leukemia.

Donor cell leukemia is a very rare cause of relapse after allogeneic hematopoietic cell transplantation (alloHCT). Herein, we describe an unprecedented case of donor cell-derived chronic myelomonocytic leukemia (CMML) presenting seven years after a 51-year-old man received a matched-related alloHCT from his 59-year-old brother for T-cell acute lymphoblastic leukemia.

Salvage Therapy With Multikinase Inhibitors and Immunotherapy in Advanced Adrenal Cortical Carcinoma.

BACKGROUND: Median overall survival is 12 to 15 months in patients with metastatic adrenal cortical carcinoma (ACC). Etoposide, doxorubicin, and cisplatin with or without the adrenolytic agent mitotane is considered the best first-line approach in this context, but has limited activity and no curative potential; additional salvage therapeutic options are needed. METHODS: Fifteen total patients with recurrent/metastatic ACC were treated with single-agent multikinase inhibitors (MKI) (n = 8), single-agent PD-1 inhibition (n = 8), or cytotoxic chemotherapy plus PD-1 inhibition (n = 4) at our institution as later-line systemic therapies in efforts to palliate disease and attempt to achieve a therapeutic response when not otherwise possible using standard approaches. RESULTS: Two of 8 patients (25%) treated with single-agent MKI achieved a partial response (PR), including 1 PR lasting 23.5 months. Another 3 patients (38%) had stable disease (SD); median progression-free survival (PFS) with single-agent MKI was 6.4 months (95% confidence interval [CI] 0.8-not reached). On the other hand, 2 of 12 patients (17%) treated with PD-1 inhibitors (either alone or in combination with cytotoxic chemotherapy) attained SD or better, with 1 patient (8%) achieving a PR; median PFS was 1.4 months (95% CI 0.6-2.7). CONCLUSIONS: Our single-institution experience suggests that select ACC patients respond to late-line MKI or checkpoint inhibition despite resistance to cytotoxic agents. These treatments may be attractive to ACC patients with limited other therapeutic options. The use of MKI and immunotherapy in ACC warrants prospective investigation emphasizing parallel correlative studies to identify biomarkers that predict for response.

The impact of re-induction prior to salvage autologous stem cell transplantation in multiple myeloma.

Autologous stem cell transplantation (ASCT) is an integral component of the therapeutic arsenal in multiple myeloma. Given that overall survival (OS) is comparable between patients receiving up-front or delayed ASCT, some opt to collect stem cells and postpone transplant until the time of disease progression (i.e., salvage ASCT). It is unknown if induction should be repeated prior to salvage ASCT, or if patients should proceed directly. We identified 234 patients who underwent salvage ASCT at our institution: 188 (80%) were re-induced, whereas 46 (20%) proceeded directly without re-induction. There was no significant difference in time to next therapy (TNT) or OS from Day 0 between the two groups. Patients who were re-induced had a nonsignificant trend towards a higher rate of complete response post-ASCT (45 vs. 33%, p = .12). In multivariate models, re-induction did not affect TNT/OS. In the subgroup of 188 patients who were re-induced, patients with relapsed/refractory disease at the time of ASCT had significantly shorter TNT/OS compared to patients with deeper pre-ASCT responses. In summary, there was no survival difference for patients who were re-induced before salvage ASCT. However, many factors affect the decision to re-induce, and prospective studies would be required to discern its role definitively.

Histone deacetylase inhibition in combination with MEK or BCL-2 inhibition in multiple myeloma.

Despite recent advances in the treatment of multiple myeloma, patients with this disease still inevitably relapse and become refractory to existing therapies. Mutations in K-RAS, N-RAS and B-RAF are common in multiple myeloma, affecting 50% of patients at diagnosis and >70% at relapse. However, targeting mutated RAS/RAF via MEK inhibition is merely cytostatic in myeloma and largely ineffective in the clinic. We examined mechanisms mediating this resistance and identified histone deacetylase inhibitors as potent synergistic partners. Combining the MEK inhibitor AZD6244 (selumetinib) with the pan-histone deacetylase inhibitor LBH589 (panobinostat) induced synergistic apoptosis in RAS/RAF mutated multiple myeloma cell lines. Interestingly, this synergy was dependent on the pro-apoptotic protein BIM. We determined that while single-agent MEK inhibition increased BIM levels, the protein remained sequestered by antiapoptotic BCL-2 family members. LBH589 dissociated BIM from MCL-1 and BCL-XL, which allowed it to bind BAX/BAK and thereby initiate apoptosis. The AZD6244/LBH589 combination was specifically active in cell lines with more BIM:MCL-1 complexes at baseline; resistant cell lines had more BIM:BCL-2 complexes. Those resistant cell lines were synergistically killed by combining the BH3 mimetic ABT-199 (venetoclax) with LBH589. Using more specific histone deacetylase inhibitors, i.e. MS275 (entinostat) and FK228 (romidepsin), and genetic methods, we determined that concomitant inhibition of histone deacetylases 1 and 2 was sufficient to synergize with either MEK or BCL-2 inhibition. Furthermore, these drug combinations effectively killed plasma cells from myeloma patients ex vivo Given the preponderance of RAS/RAF mutations, and the fact that ABT-199 has demonstrated clinical efficacy in relapsed/refractory multiple myeloma, these drug combinations hold prom ise as biomarker-driven therapies.

Comparable outcomes using propylene glycol-free melphalan for autologous stem cell transplantation in multiple myeloma.

Autologous stem cell transplantation (ASCT) remains a mainstay in the treatment of multiple myeloma (MM). While the procedure is generally safe, toxicities associated with high-dose melphalan conditioning are common and significantly affect patient quality of life. Recently, a propylene glycol-free melphalan formulation (PG-free MEL; Evomela®) was approved by the United States Food and Drug Administration as an ASCT-conditioning regimen for MM. PG-free MEL is more soluble and stable than propylene glycol-solubilized melphalan (PG-solubilized MEL; Alkeran®). As such, there is speculation that it could decrease toxicities and increase the efficacy of ASCT. We compared the outcomes of patients conditioned with PG-free MEL (n = 216) to PG-solubilized MEL (n = 200) at our institution. The baseline characteristics were similar between the two groups. After Day +0, there were no differences in terms of hospitalizations, neutropenic fevers, intravenous granisetron requirement, World Health Organization grade ≥ 2 oral/esophageal mucositis, intravenous fluid requirement, or narcotic requirement. However, PG-free MEL patients had a higher incidence of diarrhea, which was mostly C. difficile-negative (82% vs. 71%, P = 0.015*). Day + 100 hematologic responses and progression-free survival after ASCT were comparable. In summary, we demonstrate that switching to PG-free MEL did not significantly reduce short-term complications of ASCT or improve outcomes in MM.

Utility of adjuvant chemotherapy in patients receiving surgery and adjuvant radiotherapy for primary treatment of esthesioneuroblastoma.

BACKGROUND: Past research established that surgery plus adjuvant radiotherapy (S + AR) improves overall survival (OS) in esthesioneuroblastoma (ENB). However, it is unknown if the addition of adjuvant chemotherapy (AC) further improves survival. The primary objective of this study was to compare survival among patients treated with S + AR alone to patients who underwent S + AR + AC. METHODS: Retrospective review of patient records. RESULTS: Thirty-eight patients met inclusion criteria for either S + AR or S + AR + AC treatment groups. The S + AR + AC group contained more patients with Kadish stage D disease, dural invasion, and positive histologic margins postsurgery. All S + AR + AC patients received platinum-based regimens, combined with etoposide in 67%. OS and recurrence-free survival did not differ between the two groups, even when restricting the analysis to patients with Kadish stages B and C disease. CONCLUSION: Patients who received platinum-based AC did not exhibit improved survival compared to S + AR alone. Further investigation, preferably prospective, into the optimal use of systemic therapy in ENB is warranted.

Elderly acute lymphoblastic leukemia: a Mayo Clinic study of 124 patients.

Poor outcomes in elderly acute lymphoblastic leukemia (ALL) are well recognized, but the contributors are ill-defined. We characterized 124 patients ≥60 years old at our institution. The majority (n = 102, 82%) were treated with intensive chemotherapy. Of these, 8/102 (8%) died within the first 100 days; 92/102 (90%) achieved complete remission (CR/CRi). Only 31/124 (25%) patients underwent allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) for the entire cohort was 19.8 months. In a multivariate analysis, ECOG performance status ≥2, high white blood cell count, and high lactate dehydrogenase (at time of diagnosis) negatively influenced OS (p<.01). In a subgroup analysis of the intensive treatment group, BCR-ABL1+ patients had markedly better OS (hazard ratio 0.3, 95% CI 0.1-0.7; p<.01). In summary, despite few early deaths and a high CR/CRi rate, elderly ALL continues to have a poor prognosis, underscoring the need for more effective therapies.

Round Table on Malignant Hyperthermia in Physically Active Populations: Meeting Proceedings.

CONTEXT: Recent case reports on malignant hyperthermia (MH)-like syndrome in physically active populations indicate potential associations among MH, exertional heat stroke (EHS), and exertional rhabdomyolysis (ER). However, an expert consensus for clinicians working with these populations is lacking. OBJECTIVE: To provide current expert consensus on the (1) definition of MH; (2) history, etiology, and pathophysiology of MH; (3) epidemiology of MH; (4) association of MH with EHS and ER; (5) identification of an MH-like syndrome; (6) recommendations for acute management of an MH-like syndrome; (7) special considerations for physically active populations; and (8) future directions for research. SETTING: An interassociation task force was formed by experts in athletic training, exercise science, anesthesiology, and emergency medicine. The "Round Table on Malignant Hyperthermia in Physically Active Populations" was convened at the University of Connecticut, Storrs, September 17-18, 2015. CONCLUSIONS: Clinicians should consider an MH-like syndrome when a diagnosis of EHS or ER cannot be fully explained by clinical signs and symptoms presented by a patient or when recurrent episodes of EHS or ER (or both) are unexplained. Further research is required to elucidate the genetic and pathophysiological links among MH, EHS, and ER.