Alex Ganetsky

Ruxolitinib: a new treatment option for myelofibrosis.

Myelofibrosis is a myeloproliferative neoplasm characterized by bone marrow fibrosis and extramedullary hematopoiesis. Evolution of myelofibrosis can lead to life‐threatening complications, including transformation to leukemia, thrombotic events, and hemorrhagic episodes. The only curative therapy for myelofibrosis is allogeneic hematopoietic stem cell transplantation. Because this disease manifests primarily in the older population, many patients diagnosed with myelofibrosis are not considered medically fit for such aggressive therapy. Other available medical therapies do not halt disease progression; instead, current treatment strategies have focused on targeting specific symptomology, although with limited efficacy. The lack of effective treatment options for patients with myelofibrosis has rendered this orphan disease state an unmet medical need, and novel approaches to improve outcomes are necessary. Emerging research has identified numerous molecular mutations in patients with myelofibrosis, making this disease a potential candidate for molecularly targeted therapy. The most prevalent mutation identified is a gain‐of‐function mutation in the Janus kinase (JAK) family, JAK2 V617F, which has been identified in more than half of patients with myelofibrosis. This mutation results in a constitutively active JAK‐signal transducer and activator of transcription pathway resulting in dysregulated cellular proliferation and hematopoiesis. Ruxolitinib is a small‐molecule inhibitor of JAK1 and JAK2 and recently became the first drug approved by the United States Food and Drug Administration for the treatment of symptomatic intermediate‐ or high‐risk myelofibrosis. In clinical trials, ruxolitinib demonstrated promising efficacy in reducing splenomegaly and myelofibrosis‐related symptoms. However, ruxolitinib did not demonstrate disease‐modifying potential and is not considered a curative therapeutic option. Adverse events associated with ruxolitinib are primarily hematologic, with thrombocytopenia and anemia being the most common toxicologic events identified. Future research will shed light on whether ruxolitinib in combination with other treatments will further enhance outcomes in myelofibrosis.

Gastroenteropancreatic Neuroendocrine Tumors: Update on Therapeutics

OBJECTIVE: To review the available literature addressing the treatment of pancreatic neuroendocrine tumors (PNETs) and carcinoid tumors. DATA SOURCES: Relevant literature was identified by a PubMed search (January 1977-December 2011) of English-language literature using the terms gastroenteropancreatic neuroendocrine tumor, pancreatic neuroendocrine, carcinoid, and pancreatic islet cell tumor. STUDY SELECTION AND DATA EXTRACTION: All published studies and abstracts, as well as relevant consensus guidelines, evaluating the current literature about PNETs and carcinoid tumors were included. DATA SYNTHESIS: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a genetically diverse group of complex malignancies with varying biological and clinical courses. Historically believed to be rare, recent epidemiologic data suggest their incidence is rising. Two of the most commonly diagnosed GEP-NETs are PNETs and carcinoid tumors. Both subtypes are well-differentiated tumors and present as low or intermediate grade. The systemic manifestations of PNETs and carcinoid tumors are diverse and are related to the secretion of affected hormones and biogenic amines. Surgical resection of localized disease remains the only curative option. However, the utility of this approach is limited because most patients are diagnosed with advanced disease. Recent advances have led to an improvement in outcomes in patients with PNETs and carcinoid tumors. This review describes traditional therapies as well as emerging strategies being investigated to help manage these cancers. Treatment of poorly differentiated GEP-NETs is beyond the scope of this review. CONCLUSIONS: The advent of new therapies for PNETs and carcinoid tumors has introduced a paradigm shift in the management of this heterogeneous malignancy.

The Role of Decitabine for the Treatment of Acute Myeloid Leukemia

OBJECTIVE: To review the available literature addressing the role of decitabine for the treatment of acute myeloid leukemia (AML). DATA SOURCES: Relevant literature was identified by a PubMed search (January 1970-March 2012) of English-language literature using the terms decitabine, acute myeloid leukemia, and DNA methyltransferase inhibitors. STUDY SELECTION AND DATA EXTRACTION: All published studies and abstracts, as well as relevant consensus guidelines, evaluating the current literature about the role of decitabine for the treatment of AML were included. DATA SYNTHESIS: Decitabine has been evaluated for the treatment of AML in several different settings. In patients with newly diagnosed AML who are not candidates for standard remission induction chemotherapy, a Phase 2 trial of decitabine administered for 5 days per cycle demonstrated a 24% complete remission rate (CR). A subsequent Phase 3 trial comparing decitabine and low-dose cytarabine or best supportive care in a similar patient population showed a greater CR rate (18% vs 8%; p = 0.001) but no overall survival benefit. A Phase 2 trial demonstrated a 47% CR rate with decitabine initially administered for 10 days per cycle, with subsequent doses customized to individual response and toxicity. This novel dosing schedule has yet to be evaluated in a Phase 3 trial. Decitabine is also being investigated for the treatment of relapsed/refractory AML and as bridge therapy to allogeneic hematopoietic stem cell transplantation. CONCLUSIONS: Decitabine offers a promising alternative therapeutic option for patients with AML who are not candidates for standard remission induction chemotherapy. Because of its acceptable safety profile, research is investigating the clinical benefit of decitabine in combination with other antileukemic therapies. The potential roles of decitabine in the treatment of AML continue to be explored in numerous clinical trials.

Ibrutinib-induced pneumonitis in patients with chronic lymphocytic leukemia.

To the editor: Chronic lymphocytic leukemia (CLL) is a B-cell lymphoproliferative disorder partly dependent on the B-cell receptor (BCR) signaling pathway. The novel BCR signal transduction inhibitor ibrutinib has emerged as an effective therapeutic agent for CLL.[1][1] Ibrutinib covalently binds

The Promising Impact of Ibrutinib, a Bruton's Tyrosine Kinase Inhibitor, for the Management of Lymphoid Malignancies

Lymphoid malignancies comprise a heterogeneous group of disorders originating from clonal proliferation of B or T lymphocytes. Treatment of lymphoid neoplasms has traditionally been pursued with cytotoxic chemotherapy. To improve efficacy and ameliorate the adverse effects associated with classic chemotherapy, molecularly targeted therapy has been developed. At the forefront of clinical development is ibrutinib, an inhibitor of Brutons tyrosine kinase (Btk). Btk is a protein tyrosine kinase that plays an important role in regulating B‐cell signaling. Dysregulated Btk results in uncontrolled B‐lymphocyte proliferation, differentiation, and survival. Ibrutinib is currently being studied in numerous malignancies of lymphoid origin including chronic lymphocytic leukemia, mantle cell lymphoma, non‐Hodgkin lymphoma, follicular lymphoma, and multiple myeloma. Thus far, ibrutinib has demonstrated very promising results in treatment‐naive patients as well as those with relapsed or refractory disease with an acceptable safety profile. In this article, we describe the pharmacology, efficacy, and toxicity profile of ibrutinib and depict the potential role that ibrutinib will play in the treatment paradigm of lymphoid neoplasms.

Spontaneous Subcapsular Splenic Hematoma Associated with Filgrastim in a Patient Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

OBJECTIVE To report the development of a spontaneous subcapsular splenic hematoma following filgrastim administration in a patient undergoing an allogeneic hematopoietic stem cell transplant. CASE SUMMARY A 60-year-old female with myelodysplastic syndrome was admitted for a reduced-intensity allogeneic hematopoietic stem cell transplant from an unrelated donor. She received filgrastim 5 μg/kg starting on day 1 to accelerate neutrophil recovery. On day 5, she began reporting severe left chest-wall pain. Contrast-enhanced computed tomography of the abdomen/pelvis revealed a spontaneous subcapsular splenic hematoma. Upon discontinuation of filgrastim, the pain fully resolved. The patient was subsequently rechallenged with filgrastim, which led to recurrence of the left-sided chest-wall pain. Filgrastim was discontinued and the patient reported resolution of the pain. DISCUSSION Filgrastim has been associated with splenic hematoma and splenic rupture, predominantly in healthy donors undergoing mobilization of peripheral blood stem cells. Although splenic rupture attributed to filgrastim in a patient undergoing allogeneic hematopoietic stem cell transplantation has been reported, to our knowledge, this is the first case report to establish causality. Using the Naranjo probability scale, an objective causality assessment revealed that the adverse drug event was highly probable. CONCLUSIONS Although filgrastim-induced splenomegaly, splenic hematomas, and splenic rupture are rare, clinicians working in the bone marrow transplant setting should be cognizant of the potential of growth factors to cause these adverse events.

Challenges around Access to and Cost of Life-Saving Medications after Allogeneic Hematopoietic Cell Transplantation for Medicare Patients

Hematopoietic cell transplantation (HCT) is an expensive, medically complicated, and potentially life-threatening therapy for multiple hematologic and nonhematologic disorders with a prolonged trajectory of recovery. Similar to financial issues in other cancer treatments, adverse financial consequences of HCT are emerging as an important issue and may be associated with poor quality of life and increased distress in HCT survivors. Prescription medicine coverage for HCT for Medicare and some Medicaid beneficiaries, especially in the long-term, remains suboptimal because of inadequate payer formularies or prohibitive copays. With an increasing number of older patients undergoing HCT and improvement in the overall survival after HCT, the problem of financial burden faced by Medicare beneficiaries with fixed incomes is going to worsen. In this article, we describe the typical financial burden borne by HCT recipients based on estimated copayment amounts attached to the categories of key medications as elucidated through 2 case studies. We also suggest some possible solutions for consideration to help these patients and families get through the HCT by minimizing the financial burden from essential medications needed during the post-HCT period.

Nelarabine, cyclosphosphamide and etoposide for adults with relapsed T-cell acute lymphoblastic leukaemia and lymphoma

Despite improvements in first-line treatment of T-cell acute lymphoblastic leukaemia (T-ALL) and lymphoma (T-LBL), the prognosis for patients with primary refractory or relapsed T-ALL/T-LBL remains dismal. Fewer than 10% of these patients experience long-term survival, which is dependent on successful bridge to allogeneic stem cell transplantation (SCT) (Fielding et al, 2007). Nelarabine received accelerated US Food and Drug Administration approval in 2005 for the treatment of patients with relapsed or refractory T-ALL/T-LBL, with single agent efficacy demonstrated in both adults and children (Berg et al, 2005; DeAngelo et al, 2007; Gokbuget et al, 2011). Neurological toxicity – characterized by mental status change, seizures or neuropathy – occurs in 16–72% of patients receiving single agent nelarabine and may be worsened with concomitant intrathecal or radiation therapy, active central nervous system (CNS) disease, or history of neuropathy (Berg et al, 2005; Kurtzberg et al, 2005; DeAngelo et al, 2007; Gokbuget et al, 2011). In an attempt to improve response rates, Commander et al (2010) administered nelarabine in sequential combination with cyclophosphamide and etoposide (NCE) to children with relapsed or refractory T-ALL/T-LBL; all seven patients responded with the majority achieving complete remission (CR), facilitating the bridge to SCT. Neurological toxicity was common (six of seven patients) but no grade IV neurotoxicity was reported. A follow-up multicentre study of NCE in children is underway (Whitlock et al, 2014). The sequential combination of NCE has not been reported in adults. Here, we describe the administration of NCE as salvage therapy for adults with relapsed T-ALL/T-LBL. We identified five patients (≥18 years old) treated with NCE at our centre for first relapse of T-ALL (n = 2) or T-LBL (n = 3) (Table I). NCE was administered sequentially as per Commander et al (2010) (nelarabine 650 mg/m daily days 1–5; etoposide 100 mg/m plus cyclophosphamide 440 mg/ m daily on days 7–11), or in the reverse order (Commander et al, 2010); intrathecal chemotherapy was not generally administered concurrently with nelarabine to the reduce risk for neurotoxicity. Median age at relapse was 58 years (range 50–63). One patient had relapsed after SCT. No patient had CNS disease at diagnosis or relapse. NCE was the first salvage regimen in 4 of 5 patients. Of the five patients treated, three achieved CR after 1 or 2 cycles of NCE. Remission was confirmed via bone marrow biopsy, and positron emission tomography-computerized tomography where appropriate (T-LBL patients). There was no assessment for minimal residual disease. The 2 T-LBL patients who achieved CR were successfully bridged to SCT; Patient 2 – with first relapse <1 year from diagnosis – relapsed again 2 months after reduced intensity SCT while Patient 4 – first relapse 7 years from diagnosis – continues in remission 8 months after myeloablative SCT. The third responding patient (Patient 1) progressed during her third cycle of NCE prior to opportunity for curative SCT. The remaining two patients died from toxicity prior to disease reassessment. One treatment-related death (Patient 3) was due to sepsis (day +28). While this event was certainly therapy-related, infectious complications are not unique to NCE. The second patient (Patient 5) developed progressive neuromuscular (including diaphragmatic) weakness leading to respiratory failure on day +44. Neuromuscular weakness in this case was probably due to nelarabine neurotoxicity; a similar Guillan-Barre-like syndrome was reported by Gokbuget et al (2011). This patient had a history of grade 3 drug-related peripheral neuropathy, and was the only patient in our cohort to receive intrathecal therapy concurrently with nelarabine, supporting the approach of Commander et al (2010), of separating nelarabine administration from intrathecal chemotherapy. There was only one other episode of grade II neurotoxicty reported among the five patients (8 cycles of therapy). Our experience is too limited to make definitive conclusions regarding the efficacy and safety of nelarabine combination therapy compared to nelarabine monotherapy; however, we are intrigued that all three evaluable patients achieved a CR after 1–2 cycles of therapy. Two of the three patients obtained remissions durable enough to allow subsequent SCT; one of the two transplanted patients is in continued remission 8 months later. We believe our experience provides a rationale for the study of nelarabine in combination (as NCE) as a remission induction for adults with relapsed or refractory T-ALL/T-LBL with the goal to bridge to SCT (or donor lymphocyte infusion in post-SCT relapses). There have been many recent advances in salvage options for B-ALL (Frey & Luger, 2015), but new treatment options are desperately need for immature T-cell malignancies. Correspondence

A validation of clinical data captured from a novel Cancer Care Quality Program directly integrated with administrative claims data

Background Data from a Cancer Care Quality Program are directly integrated with administrative claims data to provide a level of clinical detail not available in claims-based studies, and referred to as the HealthCore Integrated Research Environment (HIRE)-Oncology data. This study evaluated the validity of the HIRE-Oncology data compared with medical records of breast, lung, and colorectal cancer patients. Methods Data elements included cancer type, stage, histology (lung only), and biomarkers. A sample of 300 breast, 200 lung, and 200 colorectal cancer patients within the HIRE-Oncology data were identified for medical record review. Statistical measures of validity (agreement, positive predictive value [PPV], negative predictive value [NPV], sensitivity, specificity) were used to compare clinical information between data sources, with medical record data considered the gold standard. Results All 300 breast cancer records reviewed were confirmed breast cancer, while 197 lung and 197 colorectal records were confirmed (PPV =0.99 for each). The agreement of disease stage was 85% for breast, 90% for lung, and 94% for colorectal cancer. The agreement of lung cancer histology (small cell vs non-small cell) was 97%. Agreement of progesterone receptor, estrogen receptor, and human epidermal growth factor receptor 2 status biomarkers in breast cancer was 92%, 97%, and 92%, respectively; epidermal growth factor receptor and anaplastic lymphoma kinase agreement in lung was 97% and 92%, respectively; and agreement of KRAS status in colorectal cancer was 95%. Measures of PPV, NPV, sensitivity, and specificity showed similarly strong evidence of validity. Conclusion Good agreement between the HIRE-Oncology data and medical records supports the validity of these data for research.

Gut microbiota modulates adoptive cell therapy via CD8α dendritic cells and IL-12

Adoptive T cell therapy (ACT) is a promising new modality for malignancies. Here, we report that adoptive T cell efficacy in tumor-bearing mice is significantly affected by differences in the native composition of the gut microbiome or treatment with antibiotics, or by heterologous fecal transfer. Depletion of bacteria with vancomycin decreased the rate of tumor growth in mice from The Jackson Laboratory receiving ACT, whereas treatment with neomycin and metronidazole had no effect, indicating the role of specific bacteria in host response. Vancomycin treatment induced an increase in systemic CD8α+ DCs, which sustained systemic adoptively transferred antitumor T cells in an IL-12-dependent manner. In subjects undergoing allogeneic hematopoietic cell transplantation, we found that oral vancomycin also increased IL-12 levels. Collectively, our findings demonstrate an important role played by the gut microbiota in the antitumor effectiveness of ACT and suggest potentially new avenues to improve response to ACT by altering the gut microbiota.