Prithviraj Bose

Treatment of Relapsed/Refractory Acute Myeloid Leukemia

Opinion statementApproximately 40–45% of younger and 10–20% of older adults with acute myeloid leukemia (AML) will be cured with current standard chemotherapy. The outlook is particularly gloomy for patients with relapsed and/or refractory disease (cure rates no higher than 10%). Allogeneic hematopoietic stem cell transplantation (HSCT), the only realistic hope of cure for these patients, is an option for only a minority. In recent years, much has been learned about the genomic and epigenomic landscapes of AML, and the clonal architecture of both de novo and secondary AML has begun to be unraveled. These advances have paved the way for rational drug development as new “drugable” targets have emerged. Although no new drug has been approved for AML in over four decades, with the exception of gemtuzumab ozogamycin, which was subsequently withdrawn, there is progress on the horizon with the possible regulatory approval soon of agents such as CPX-351 and midostaurin, the Food and Drug Administration “breakthrough” designation granted to venetoclax, and promising agents such as the IDH inhibitors AG-221 and AG-120, the smoothened inhibitor glasdegib and the histone deacetylase inhibitor pracinostat. In our practice, we treat most patients with relapsed/refractory AML on clinical trials, taking into consideration their prior treatment history and response to the same. We utilize targeted sequencing of genes frequently mutated in AML to identify “actionable” mutations, e.g., in FLT3 or IDH1/2, and incorporate small-molecule inhibitors of these oncogenic kinases into our therapeutic regimens whenever possible. In the absence of actionable mutations, we rationally combine conventional agents with other novel therapies such as monoclonal antibodies and other targeted drugs. For fit patients up to the age of 65, we often use high-dose cytarabine-containing backbone regimens. For older or unfit patients, we prefer hypomethylating agent-based therapy. Finally, all patients with relapsed/refractory AML are evaluated for allogeneic HSCT.

Pathways and mechanisms of venetoclax resistance

Abstract The approval of venetoclax, a ‘BH3-mimetic’ antagonist of the BCL-2 anti-apoptotic protein, for chronic lymphocytic leukemia represents a major milestone in translational apoptosis research. Venetoclax has already received ‘breakthrough’ designation for acute myeloid leukemia, and is being studied in many other tumor types. However, resistance to BCL-2 inhibitor monotherapy may rapidly ensue. Several studies have shown that the other two major anti-apoptotic BCL-2 family proteins, BCL-XL and MCL-1, are the main determinants of resistance to venetoclax. This opens up possibilities for rationally combining venetoclax with other targeted agents to circumvent resistance. Here, we summarize the most promising combinations, and highlight those already in clinical trials. There is also increasing recognition that different tumors display different degrees of addiction to individual BCL-2 family proteins, and of the need to refine current ‘BH3 profiling’ techniques. Finally, the successful clinical development of potent and selective antagonists of BCL-XL and MCL-1 is eagerly awaited.

JAK2 inhibitors for myeloproliferative neoplasms: What is next?

Since its approval in 2011, the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant or intolerant polycythemia vera (PV) is steadily increasing. Several other JAK2 inhibitors have entered clinical testing, but none have been approved and many have been discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, in which survival is short. Many such combinations are being explored, as are other novel agents, some of which could successfully be combined with JAK2 inhibitors in the future. In addition, new JAK2 inhibitors with the potential for less myelosuppression continue to be investigated. Given the proven safety and efficacy of ruxolitinib, it is likely that ruxolitinib-based combinations will be a major way forward in drug development for MF. If approved, less myelosuppressive JAK2 inhibitors such as pacritinib or NS-018 could prove to be very useful additions to the therapeutic armamentarium in MF. In PV, inhibitors of histone deacetylases and human double minute 2 have activity, but their role, if any, in the future treatment algorithm is uncertain, given the availability of ruxolitinib and renewed interest in interferons. Ruxolitinib is in late-phase clinical trials in essential thrombocythemia, in which it could fill an important void for patients with troublesome symptoms.

Investigational histone deacetylase inhibitors (HDACi) in myeloproliferative neoplasms.

ABSTRACT Introduction: The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) mainly comprise polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF, primary or post-PV/ET). Therapy in PV and ET focuses on minimizing thrombosis and bleeding risk, while in MF, prolongation of survival is an important goal. Different cytoreductive agents are employed in high risk PV and ET, while the JAK inhibtior ruxolitinib is the cornerstone of therapy in MF. Histone deacetylase inhibitors (HDACi) are pleiotropic agents with diverse epigenetic and non-epigenetic actions, selectively in transformed cells. A number of HDACi have been or are being investigated in MPN. Areas covered: The mechanisms of action of HDACI in neoplastic cells are summarized, and the preclinical rationale and data supporting their development in MPN specifically examined, particularly their synergism with JAK inhibitors. Major findings of clinical trials of HDACi, both alone and in combination with ruxolitinib, in MPN are then discussed, with particular attention to their toxicities and disease-modifying effects. Expert opinion: HDACi are clearly active in MPN, and there is good preclinical rationale for this. Their combination with ruxolitinib in MF is promising, but the long-term tolerability of these agents is an important concern. Further development in PV or ET appears unlikely.

The evolution and clinical relevance of prognostic classification systems in myelofibrosis

Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome‐negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by often debilitating constitutional symptoms and splenomegaly, bone marrow fibrosis and resultant cytopenias, extramedullary hematopoiesis, risk of leukemic transformation, and shortened survival. Post‐polycythemia vera and post‐essential thrombocythemia myelofibrosis represent similar entities, although some differences are being recognized. Attempts to classify patients with myelofibrosis into prognostic categories have been made since the late 1980s, and these scoring systems continue to evolve as new information becomes available. Over the last decade, the molecular pathogenesis of MPNs has been elucidated considerably, and the Janus kinase (JAK) 1/2 inhibitor ruxolitinib is the first drug specifically approved by the US Food and Drug Administration to treat patients with intermediate‐risk and high‐risk myelofibrosis. This article reviews the evolution of prognostic criteria in myelofibrosis, emphasizing the major systems widely in use today, as well as recently described, novel systems that incorporate emerging data regarding somatic mutations. Risk factors for thrombosis and conversion to MPN blast phase also are discussed. Finally, the practical usefulness of the current prognostic classification systems in terms of clinical decision making is discussed, particularly within the context of some of their inherent weaknesses. Cancer 2016;122:681–692.

Patients with post-essential thrombocythemia and post-polycythemia vera differ from patients with primary myelofibrosis

Prognostic scoring systems for primary myelofibrosis (PMF) are not accurate in patients with post-essential thrombocythemia and post-polycythemia vera myelofibrosis (PET-MF; PPV-MF). Given the paucity of data describing the clinical characteristics, disease course and outcomes of these patients, we sought to describe and compare the clinical characteristics and outcomes of 755 patients with PMF, 181 with PPV-MF, and 163 with PET-MF referred to our institution between 1984 and 2013. The median follow-up was 31 months, and 56% (n=616) patients had died. Over an observation period of 3502 person-years, 11% of patients had progression to AML, with similar rates among groups. The proportion of patients with transfusion dependency (higher in PMF), leukocytosis and systemic symptoms (higher in PPV-MF), and thrombocytopenia (higher in PMF, PPV-MF) differed among groups. Median overall survival (OS) was longest in PET-MF patients (73 mo vs 45 mo (PMF) vs 48 mo (PPV-MF), p <0.001). Stratification of OS by DIPSS was only discriminatory in patients with PMF, and it failed to distinguish higher risk patients with PPV/PET-MF. In multivariate analysis, predictors of inferior OS were higher age, anemia, systemic symptoms, thrombocytopenia, and high peripheral blasts in PMF; age, anemia, and systemic symptoms for PPV-MF; and anemia, peripheral blasts and thrombocytopenia in PET-MF. Although the clinical characteristics of PPV/PET-MF patients are not substantially different from those with PMF, their outcomes differ and prognostic scoring systems for PET/PPV-MF should be improved.

Phase 1 trial of carfilzomib (PR-171) in combination with vorinostat (SAHA) in patients with relapsed or refractory B-cell lymphomas

Abstract A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30-min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3 + 3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20 mg/m2 carfilzomib and 100 mg vorinostat (twice daily). The dose-limiting toxicities were grade 3 pneumonitis, hyponatremia, and febrile neutropenia. One patient had a partial response and two patients had stable disease. Correlative studies showed a decrease in NF-κB activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response.

A phase II trial of ruxolitinib in combination with azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms

Ruxolitinib and azacytidine target distinct disease manifestations of myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs). Patients with MDS/MPNs initially received ruxolitinib BID (doses based on platelets count), continuously in 28‐day cycles for the first 3 cycles. Azacytidine 25 mg/m2 (Day 1‐5) intravenously or subcutaneously was recommended to be added to each cycle starting cycle 4 and could be increased to 75 mg/m2 (Days 1‐5) for disease control. Azacytidine could be started earlier than cycle 4 and/or at higher dose in patients with rapidly proliferative disease or with elevated blasts. Thirty‐five patients were treated (MDS/MPN‐U, n =14; CMML, n =17; aCML, n =4), with a median follow‐up of 15.2 months (range, 1.0–41.5). All patients were evaluable by the 2015 international consortium proposal of response criteria for MDS/MPNs (ICP MDS/MPN) and 20 (57%) responded. Nine patients (45%) responded after the addition of azacytidine. A greater than 50% reduction in palpable splenomegaly at 24 weeks was noted in 9/14 (64%) patients. Responders more frequently were JAK2‐mutated (P = .02) and had splenomegaly (P = .03) compared to nonresponders. New onset grade 3/4 anemia and thrombocytopenia occurred in 18 (51%) and 19 (54%) patients, respectively, but required therapy discontinuation in only 1 (3%) patient. Patients with MDS/MPN‐U had better median survival compared to CMML and aCML (26.5 vs 15.1 vs 8 months; P = .034). The combination of ruxolitinib and azacytidine was well‐tolerated with an ICP MDS/MPN‐response rate of 57% in patients with MDS/MPNs. The survival benefit was most prominent in patients with MDS/MPN‐U.

Hyper-CVAD plus nelarabine in newly diagnosed adult T-cell acute lymphoblastic leukemia and T-lymphoblastic lymphoma

Nelarabine, a water soluble prodrug of 9‐β‐D‐arabinofuranosylguanine (ara‐G), is a T‐cell specific purine nucleoside analogue. Given its activity in relapsed and refractory T acute lymphoblastic leukemia (T‐ALL) and T lymphoblastic lymphoma (T‐LBL), we sought to define its role in the frontline treatment of adult patients. Therefore, we conducted a single arm phase 2 study to determine the safety and efficacy of nelarabine in combination with hyper‐CVAD in newly diagnosed patients. For induction/consolidation, patients received eight cycles of hyper‐CVAD alternating with high‐dose methotrexate and cytarabine plus two cycles of nelarabine given at a dose of 650 mg/m2 intravenously daily for 5 days. This was followed by thirty months of POMP maintenance chemotherapy with two additional cycles of nelarabine given instead of cycles 6 and 7 of POMP maintenance. Sixty‐seven patients, including 40 with T‐ALL and 26 with T‐LBL, were enrolled. Complete response rates in both T‐ALL and T‐LBL were 87% and 100% respectively. Grade 3 to 4 neurotoxic adverse events were reported in 5 patients. There were 21 relapses (31%) including 2 after allogeneic stem cell transplantation. Median duration of follow‐up was 42.5 months. The 3‐year complete remission duration (CRD) and overall survival (OS) rates were 66% and 65%, respectively. Compared to our historic hyper‐CVAD data, there was no survival benefit with the addition of nelarabine. In conclusion, hyper‐CVAD plus nelarabine was well tolerated and active in the frontline treatment of adult T‐ALL/LBL patients.

Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial

Summary Background Disease-related symptoms impair the quality of life of countless patients with chronic lymphocytic leukemia (CLL) who do not require systemic therapy. Currently available therapies are not specifically aimed at symptom control. Because stimulation of the B-cell receptor activates Janus kinase (JAK)-2 in CLL cells and the JAK2 inhibitor ruxolitinib improves symptoms of patients with myelofibrosis, we hypothesized that ruxolitinib would improve disease-related symptoms in CLL patients. Methods Ruxolitinib (10 mg twice daily) was administered to symptomatic CLL patients who did not require systemic therapy for CLL. Scores on the brief fatigue inventory (BFI), CLL module of the MD Anderson symptom inventory (MDASI) and symptom-associated interference in daily activities (interference score; IS), were assessed prior to treatment and after 3 months of treatment. Plasma cytokine/chemokine levels were measured at baseline and at 3 months. Findings Forty-one CLL patients (25 untreated and 16 previously treated) were enrolled. Thirty-two (78%) of the participants experienced ≥20% reduction in the average BFI score or in the average MDASI score. 59% of the participants had ≥2 units reduction in worst fatigue score in 24 hours as assessed by the BFI. The mean percentage reductions in BFI, MDASI, and IS scores were >42% (p<0.0001). Improvements in the three symptom scores correlated with reductions in levels of IL-6, C-reactive protein, CXCL10, osteopontin, TNF-α, ICAM-1/CD54, VCAM-1/CD106, and beta-2 microglobulin. Furthermore, treatment with ruxolitinib increased and then decreased lymphocyte counts to baseline levels or lower. Grade 3/4 cytopenias were recorded in three patients. Interpretation In CLL patients, ruxolitinib significantly improved disease-related symptoms, reduced cytokine and chemokine levels, and increased and then decreased lymphocyte counts, likely through mobilization followed by apoptosis of CLL cells. Further studies aimed at testing the therapeutic efficacy of ruxolitinib in CLL are warranted. Funding Supported by the Incyte Corp., MD Anderson Cancer Center Support Grant CA016672 and Award Number P01 CA049639 from the National Cancer Institute.