How Do I Treat…?
Practical perspectives on cancer treatment by thought leaders, explaining how they would approach the treatment of a patient in their area of expertise.
Tuesday, December 15, 2015
Prithviraj Bose, MD (left), is Assistant Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center; and Srdan VerstoVSEK, MD, PHD, is Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center.
Amongst the classic Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-negative MPNs), primary myelofibrosis (PMF) is associated with the poorest outcome. Most recent estimates of median survival range from six to seven years. Approximately 90 percent of patients have an identifiable “driver” mutation--JAK2 V617F in 50 to 60 percent of patients, CALR exon 9 mutations in 20 to 30 percent, and MPL mutations in five to 10 percent.
About 10 percent of patients have “triple negative” disease, which has been associated with inferior outcomes. Pathologic hallmarks of PMF include megakaryocyte proliferation and atypia and varying degrees of reticulin or collagen fibrosis in the bone marrow and peripheral blood leukoerythroblastosis.
Typical clinical features include anemia, splenomegaly and a range of constitutional symptoms. Treatment is directed at improving these clinical features, as well as changing the natural course of the disease and improving survival. Management of patients with post-PV/ET myelofibrosis is approached in the same way.
Assessment of Prognosis and Symptom Burden
A number of prognostic scoring systems for PMF have been developed over the years. In the clinic, we typically use the International Prognostic Scoring System for the purposes of prognostication in patients at diagnosis and the Dynamic IPSS at later time points, as these models have been the most extensively validated and rely on easily available clinical information: age, hemoglobin level, leukocyte count, constitutional symptoms and presence of circulating blasts.
However, it is important to recognize the importance of emerging information on the impact of both driver and other somatic mutations, both in the terms of genes affected and the number of mutations. For example, CALR mutations favorably impact prognosis, while ASXL1 mutations adversely affect survival, as does an increased number of mutations.
New prognostic models incorporating molecular information (e.g., MIPSS) have been presented, but are not yet ready for prime time. Because constitutional symptoms represent a major burden for patients with PMF or post-PV/ET MF and can be substantially alleviated with the use of JAK inhibitors, we routinely inquire about the presence and severity of fatigue, inactivity, night sweats, itching, fever, weight loss, bone pain, early satiety, and abdominal discomfort.
Our Overall Approach to Therapy
For low-risk patients, we recommend observation only. For intermediate- and high-risk patients with symptomatic splenomegaly or troublesome MF-related systemic symptoms, we use ruxolitinib. In patients whose only disease manifestation is anemia, we use anti-anemia medications.
In accordance with the European Group for Blood and Marrow Transplantation (EBMT)/European LeukemiaNet (ELN) guidelines, we refer patients with intermediate-2- or high-risk disease for consultation regarding potentially curative allogeneic stem cell transplantation (allo-SCT). Selected intermediate-1-risk patients--such as those with high-risk genomic abnormalities; circulating blasts >5%; or refractory, transfusion-dependent anemia--are also referred for consultation regarding allo-SCT.
The optimal duration of ruxolitinib therapy before allo-SCT is currently unknown and is the subject of active investigation.
How We Use Ruxolitinib
It is critical to recognize the central role of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway and its universal activation across the spectrum of Ph-negative MPNs, irrespective of the mutation status of the JAK2 gene.
Ruxolitinib is highly effective in ameliorating constitutional symptoms and reducing spleen size in JAK2-mutated and -–wild type patients alike. In the pivotal COMFORT-I study, as well as upon longer follow-up of the COMFORT-II study, ruxolitinib improved overall survival when compared with placebo or best-available therapy, respectively.
Of particular importance, reductions in spleen size, which are dose-dependent, correlate with the survival benefit of the drug. In general, we dose ruxolitinib on-label--i.e., according to the patient’s platelet count.
In situations where it may be necessary to start with a lower dose of the drug--e.g., a patient with significant thrombocytopenia--we believe it is important to titrate up the dose as quickly as possible so as to achieve the best spleen response obtainable, whereas 10 mg twice a day appears to be sufficient to obtain relief of constitutional symptoms.
Although anemia may initially worsen on ruxolitinib, hemoglobin levels tend to improve and stabilize over time, and anemia is rarely a reason to discontinue the drug.
If ruxolitinib has to be discontinued in a patient responding well to it, it should not be done abruptly as this can lead to a rapid and profound return of symptoms. While occasional clonal remissions have been reported, we do not recommend serial measurement of the JAK2 V617F allele burden or bone marrow biopsies to check fibrosis grade during therapy with ruxolitinib.
How We Treat Anemia
Specific treatments for anemia of MF include erythropoietin-stimulating agents (ESAs), danazol, and immunomodulatory drugs (Imids). They may be combined with ruxolitinib in patients who have both symptomatic splenomegaly/constitutional symptoms and anemia.
A typical starting dose of danazol is 200 mg orally twice a day. The drug is contraindicated in men with a history of prostate cancer. Most responses to ESAs and danazol are seen within three to six months.
Among the Imids, in our experience, lenalidomide is the most active but causes significant cytopenias (particularly in combination with ruxolitinib) and needs to be given under strict supervision. Pomalidomide did not improve anemia response rates in a randomized placebo-controlled clinical trial; hence, we prefer low-dose thalidomide (50 mg/d) with or without prednisone (30 mg/d for the first month, 15 mg/d for the second month, 15 mg q.o.d for the third month). This dose is generally well-tolerated, even with long-term use. Anemia response rates to lenalidomide or thalidomide are in the range of 20 to 30 percent.
Overall, we try to avoid splenectomy because of its perioperative complication (infection, thrombosis, bleeding) rate, including a five to 10 percent mortality rate. However, splenectomy can be useful in selected situations--e.g., in patients with massive splenomegaly and refractory cytopenias not responsive to standard therapies. We do not usually recommend the use of splenic irradiation due to the prolonged and severe cytopenias this can cause.
For extramedullary hematopoiesis at other sites, as well as for pulmonary hypertension due to MF, low-dose radiation is the treatment of choice. Ruxolitinib has largely supplanted the use of hydroxyurea for splenomegaly.
For patients with elevated blood or bone marrow blasts, we use hypomethylating agents (HMAs), in combination with ruxolitinib if needed, to decrease blasts, followed by allo-SCT if a donor is available.
Combinations of ruxolitinib with other potentially effective anti-MF agents--e.g., histone deacetylase, hedgehog, DNA methyltransferase, and phosphatidylinositol-3-kinase inhibitors--are being evaluated in order to improve results seen with ruxolitinib alone and to obtain additional benefits (e.g., improvements in anemia or bone marrow fibrosis).
Other novel JAK inhibitors that are less myelosuppressive, such as pacritinib and momelotinib, are also in advanced phases of clinical testing.
Finally, new drugs for anemia--e.g., sotatercept, and novel compounds like immune checkpoint inhibitor--are being tested as well. Referring patients for clinical trials whenever possible continues to be of paramount importance.
Wednesday, December 9, 2015
ELIAS JABBOUR, MD (left) is Associate Professor in the Leukemia Department of the University of Texas MD Anderson Cancer Center. HAGOP M. KANTARJIAN, MD, is Professor and Chairman of the Department of Leukemia and the Samsung Distinguished University Chair in Cancer Medicine at the University of Texas MD Anderson Cancer Center.
Acute lymphoblastic leukemia (ALL) is characterized by clonal proliferation of lymphoid progenitors. Significant advances have been made in the last decade toward understanding the disease pathogenesis, refinement of prognostic groups and development of novel therapies that target specific subsets of ALL. These risk-adapted therapies are transforming the treatment strategies for adults with ALL and are beginning to result in significant improvements in survival. With the current treatment regimens, long-term survival is achieved in approximately 50 percent of patients with B-cell ALL, 50 to 60 percent of those with Philadelphia-chromosome-positive ALL, 80 percent of those with Burkitt’s leukemia, and 60 percent of those with T-ALL.
Adolescent and Young Adult (AYA) ALL
The outcomes of AYAs with ALL treated on pediatric protocols were reported to be superior to those of similar patients treated with adult protocols in historical retrospective comparisons, with one exception (HCVAD regimen). Most of the adult ALL regimens in the analysis had abandoned many of the basic therapeutic principles used in pediatric ALL, opting for shorter maintenance durations, lower dose-schedules of the non-myelosuppressive ALL drugs, and favoring AML-like strategies including autologous and allogeneic stem cell transplantation (ASCT) early in complete remission (CR).
Recently, a United States intergroup study treated 318 AYAs with a pediatric-inspired regimen (COG regimen), reporting two-year event-free and overall survival rates of 66 percent and 78 percent, respectively. A recent comparison of a pediatric Augmented Berlin-Frankfurt-Münster (ABFM) regimen (n=107) with the Hyper-CVAD -/+ rituximab (n=102) in AYA patients established similar efficacy: the rates of CR, five-year CR duration, and five-year overall survival were 93 and 98 percent, 53 and 55 percent, and 60 and 60 percent, respectively.
These were associated with different toxicity profiles--mostly asparaginase-related with ABFM and myelosuppression-related with Hyper-CVAD. Thus, for AYA patients with ALL, both approaches are equivalent.
Mature B-cell ALL
The outcome for mature B-cell ALL has improved substantially with use of short-term dose-intensive treatment programs. The addition of rituximab to chemotherapy has improved the cure rates in mature B-cell ALL. Three different studies have reported a significant improvement in the survival rates from 51 percent to 78 percent after the addition of rituximab.
Furthermore, the results of the LMBA02 randomized study confirmed the initial findings: the addition of rituximab to chemotherapy improved event-free (80% vs. 60%; p=0.046) and overall survival (84% vs. 68%; p=0.024).
To further reduce early morbidity and mortality, a pilot study investigated dose-adjusted EPOCH in combination with rituximab in 30 patients (median age of 33 years; age >40 years, 40%) diagnosed with Burkitt disease. The progression-free and overall survival rates were 95 to 100 percent and 90 to 100 percent, respectively. Of note, the majority of patients (90%) were of low- and intermediate-risk disease. Ongoing trials are assessing this regimen in mature B-cell ALL.
Precursor B-cell ALL
The addition of rituximab to the Hyper-CVAD regimen in newly diagnosed patients with Philadelphia-negative, CD20-positive ALL was evaluated, adding two doses of rituximab with each of the first four cycles of intensive chemotherapy (total of eight doses of rituximab). Rituximab was also incorporated into early and late intensification cycles (months 6 and 18 of maintenance therapy).
Among patients younger than 60 years old, the addition of rituximab improved CR duration (70% vs. 38%; P < .001%) and three-year survival rates (75% vs. 47%; P = 0.003). The German Multicenter Study Group for ALL (GMALL) also reported an improvement in the minimal residual disease (MRD) negativity, the five-year remission duration, and survival rates with the addition of rituximab to standard induction and consolidation chemotherapy in patients younger than age 55.
The addition of rituximab to chemotherapy was assessed in the GRAAL-R 2005 randomized study: the addition of rituximab improved the two-year event-free survival (EFS) rates (primary endpoint) from 52 percent to 65 percent (p=0.038) and the overall survival rates from 63 percent to 74 percent (p=0.18) after censoring for allo-SCT.
Ofatumumab, a more potent second-generation anti-CD20 monoclonal antibody is being tested in combination with Hyper-CVAD. Early results are promising, with two-year progression-free and overall survival rates of 68 percent and 87 percent, respectively.
Therapy of patients with T-cell ALL is similar to those with B-cell ALL. Nelarabine is a deoxyguanosine analog that selectively accumulates in T-cells, thus making it an intriguing compound for the management of T-ALL. The drug is currently approved as a third-line option in pediatric and adult patients with relapsed ALL, and may be of optimal use in the frontline setting.
We have developed a Hyper-CVAD/nelarabine regimen in which two cycles of nelarabine are given during consolidation and two cycles are given during maintenance. Forty-eight patients were treated so far, with a CR rate of 93 percent. With a median follow-up of 41 months, the five-year survival rate is 66 percent (for AYA < 40 years, it is 70%). These rates were 38 percent and 70 percent for patients with early T-cell precursor (ETP) and mature T-ALL, respectively.
ETP-ALL is a distinct pathobiological entity that confers a poor prognosis with use of standard intensive chemotherapy. ETP-ALL is characterized by distinct cell-surface features that readily enable diagnosis: absence of CD1a, surface CD3, and CD8 expression, weak CD5 expression, and expression of one or more myeloid-associated or stem-cell associated markers. Anti-ALL therapy followed by allogeneic stem cell transplantation should be considered in first remission in patients with ETP-ALL.
Philadelphia Chromosome (Ph)-positive ALL
The combination of cytotoxic chemotherapy with a TKI has become the standard of care in patients with Ph-positive ALL. Ponatinib is a more potent BCR-ABL1 inhibitor. It also suppresses the T315I clones, a common cause of relapse in patients with Ph-positive ALL. The combination of ponatinib with Hyper-CVAD induced CR, complete cytogenetic response, major molecular response (MMR), and complete molecular response rates of 100, 100, 95, and 70 percent, respectively. The two-year survival rate is 80 percent.
To avoid vascular toxicities, the dose of ponatinib was reduced from 45 mg to 30 mg after the first course and further reduced to 15 mg if a complete molecular response was achieved.
While allogeneic stem cell transplantation (allo-SCT) has improved the outcome of patients with Ph-positive ALL, there is now some debate as to who should be referred for allo-SCT in first CR. We evaluated the predictive value of MRD assessment in patients with Ph-positive ALL treated with combination chemotherapy and TKIs, but without an allo-SCT. Patients achieving MMR at three, six, nine, and 12 months had a better survival rate: the three-year survival rates were 67 and 47 percent (p=0.02), 67 and 50 percent (p=0.04), 67 and 49 percent (p=0.05), and 80 and 48 percent (p=0.01), in patients with and without MMR, respectively.
Therefore, MRD monitoring by PCR may identify patients in first CR in whom further consolidation with allo-SCT may not be needed.
Minimal Residual Disease (MRD)
Persistence or reappearance of MRD after induction chemotherapy is the most important adverse prognostic factor in patients with ALL and identifies chemo-refractory disease. More than 90 percent of patients who have persistent MRD after chemotherapy experience a clinical relapse, despite continued chemotherapy with a median time to relapse of four to five months.
Blinatumomab, a bispecific T-cell engaging (BiTE) antibody represents the first agent in a class that redirects host T-cells to cell surface antigen-expressing cancer cells. Blinatumomab contains the variable domains of a CD19 antibody and a CD3 antibody which are joined by a non-immunogenic linker.
In the first study, 21 patients in hematologic and morphologic CR with persistent or reappearing MRD during consolidation chemotherapy were treated with blinatumomab at 15 mcg/m2/day as a continuous infusion for 28 days every six weeks, for up to four total cycles or proceed to allogeneic stem cell transplantation if a donor was available.
MRD conversion after one cycle was noted in 16 of 20 evaluable patients (80%). In a long-term follow-up update (median observation time 33 months), 12 of the 20 patients remained in CR. The estimated three-year relapse-free survival was 60 percent. Nine patients underwent allogeneic stem cell transplantation, but interestingly, non-transplanted patients had similar favorable outcome compared with the transplant group.
In a confirmatory open-label multicenter Phase II trial in 116 patients in morphologic CR with positive MRD positive, the overall rate of conversion to the MRD negativity was 80 percent (78% occurring after one cycle of treatment). The median relapse-free and overall survival was 35 and seven months, and 40 and 12 months, for patients with negative and positive MRD after one cycle of blinatumomab. Of note, allo-SCT did not confer a survival or a relapse-free survival advantage.
In elderly patients with ALL, intensive chemotherapy results in a CR rate of 80 percent with a high rate of toxicities. One-third of patients achieving CR may die of myelosuppression-associated complications, and many relapse. The long-term cure rate among such patients is only 15 to 20 percent. The goal with our regimens is to maintain efficacy but reduce toxicity.
The early results of low-intensity Hyper-CVAD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, ara-C at 0.5 g/m2 x 4 doses) with inotuzumab ozogamycin given on Day 3 of each of the first four courses, are very promising. The overall response rate was 97 percent (CR 80%). All patients achieving a response also had a negative MRD status, 75 percent of them after one cycle. The two-year overall survival rate is 64 percent (versus 38 percent for historical data).
Molecular studies uncover gene mutations that may result in aberrant pathway activation and cell survival. ALL genomes have a lower burden of genetic alterations than many solid tumors, with focal deletions being the hallmark of lymphoid leukemia.
Using genome-wide gene-expression arrays, investigators identified patients without BCR-ABL1 fusion protein expressed from the t(9;22)(q34;q11.2) having a gene expression profile similar to BCR-ABL1 ALL. This new identity was defined as Ph-like ALL. This so-called BCR-ABL1-like disease had a poor prognosis, similar to the historical poor prognosis of Ph-positive ALL prior to the addition of BCR-ABL1 TKIs to chemotherapy for this ALL subset.
The frequency of Ph-like ALL is 10 percent among children with standard-risk ALL and as high as 25 to 30 percent among young adults with ALL. This subgroup of BCR-ABL1-like ALL is characterized by the high recurrence of a diverse repertoire of novel fusions and mutations which frequently result in enhanced tyrosine kinase and cytokine receptor signaling. This subgroup could be targeted with appropriate tyrosine kinase inhibitors.
A Phase II study assessing the combination of ruxolitinib or dasatinib with chemotherapy in patients with R/R Ph-Like ALL is ongoing. Patients who have CRLF2 overexpression by flow are eligible for the ruxolitinib arm (irrespective of the JAK2 mutation status). Patients without CRLF2 overexpression are assessed for the fusion assay. Depending on the fusion results, the patient may be eligible for the ruxolitinib (JAK2 fusions), or dasatinib (ABL2, ABL1 fusions).
Despite an exceptionally high rate of initial CR, many adults with ALL will relapse. Cytotoxic chemotherapy results in modest CR rates of 30 to 40 percent in first salvage and 10 to 20 percent in later salvages.
Few patients can be bridged to allo-SCT--five to 10 percent in some studies but as high as 30 to 40 percent in the German trials. This bridging to allo-SCT offers a chance of long-term remissions and cures (<20-30%).
Blinatumomab was first assessed in patients with positive MRD and subsequently studied in patients with relapsed/refractory (R/R) ALL. In the pivotal trial, the overall response rate (ORR; CR or CR with incomplete count recovery) within two cycles of therapy was 69 percent. The estimated median survival was 9.8 months.
In a confirmatory open-label, single-arm, multicenter Phase II study in 189 patients with relapsed/refractory disease, the ORR was 43 percent, with 80 percent of the responses occurring within the first cycle. The median response duration and overall survival were nine and six months, respectively.
Blinatumomab is currently being assessed in a Phase III trial in patients with ALL in first or second relapse randomized to either blinatumomab or an investigator’s choice chemotherapy regimen.
Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody conjugated to calecheamicin, which is a natural product of micromonospora echinospora and is significantly more toxic than chemotherapy. It binds to the minor DNA groove and causes double-strand DNA breaks resulting in cell apoptosis. Inotuzumab binds to CD22 with subnanomolar affinity, is rapidly internalized, and delivers the conjugated calecheamicin intracellularly.
We conducted two studies of inotuzumab in refractory/relapsed ALL--one with 1.3-1.8 mg/m2 single dose every 3-4 weeks (n=49), and a second with a weekly dose (0.8 mg/m2 on day 1, 0.5 mg/m2 on day 9 and day 15; every three weeks) (n=41).
In the 90 patients treated, the marrow CR rate was 55 percent. The median survival was 6.3 months. These encouraging results led to an international study comparing weekly inotuzumab with standard ALL chemotherapy in ALL Salvage 1-2. The objective response rates were 81 and 33 percent, respectively.
Among responders, the MRD-negativity rates were 78 and 28 percent, respectively. The median response duration was 4.6 versus 3.1 months (p=0.017), respectively. Inotuzumab in combination with lower-intensity Hyper-CVD chemotherapy was tested in 52 patients with R/R ALL.
The objective response rate was 77 percent; the two-year PFS and OS rates were 60 percent and 32 percent, respectively. Furthermore, the two-year survival rate was 50 percent in patients treated in Salvage 1. When compared with single-agent inotuzumab, the combination improved the two-year and median survival from 17 percent to 32 percent, and six to 11 months (p=0.03), respectively.
Due to the occurrence of veno-occlusive disease in patients treated with inotuzumab, a lower-dose schedule (50% dose reduction, 0.6 mg/m2 on Day 1 and 0.3 mg/m2 on Day 8) of single-agent inotuzumab is being explored.
Chimeric Antigen Receptor T-cells (CAR T-cells) Therapies
Harnessing the patient’s immune system to eliminate malignant cells has been an area of oncologic research for decades. Chimeric antigen receptor-modified T-cells have emerged as an effective approach for patients with lymphoid malignancies. Autologous T-cells are engineered to express a receptor directed at CD19 which mediates cytotoxicity. These cells have been noted to expand and persist in vivo: this mechanism may confer response durability.
Several pilot trials in children and adult patients with ALL reported high CR rates (70% to 90%) with an estimated 12-month survival rate of 50 to 70 percent. Severe cytokine release syndromes were reported in 30 to 40 percent of patients. Multiple Phase trials in patients with relapsed/refractory ALL are currently ongoing.
Improvements in the therapy of adult ALL are highly encouraging. Targeted therapies have been shown to improve survival when combined with conventional chemotherapy. Blinatumomab and inotuzumab have demonstrated marked activity even in multiply-refractory patients.
The role of monoclonal antibodies, the chimeric CAR-T cell therapies, and other novel targeted approaches in adult ALL continue to be defined. The majority of these agents are currently being evaluated in the salvage setting, although the most active agents will likely need to be incorporated into the frontline treatment plan to optimize efficacy and decrease toxicities.
Strategies such as these will continue to be developed and refined with the goal of further improving the cure rates in adults ALL.
Tuesday, November 24, 2015
BY COURTNEY D. DINARDO, MD, MSCE; AND FARHAD RAVANDI, MD
Standard intensive therapy for newly diagnosed patients with acute myeloid leukemia (AML) consists of the nucleoside analogue cytarabine in combination with an anthracycline as induction chemotherapy, followed by consolidation therapy with repeated cycles of high-dose cytarabine and/or stem cell transplant to maintain complete remission (CR). With such intensive chemotherapy (IC) approaches, remissions are common, but unfortunately durable long-term cures occur only in a minority of adult patients with AML. This is especially true in older patients--typically those older than 60 or 65 years of age at diagnosis--which constitute the majority of patients diagnosed with AML.
There are currently no FDA-approved therapies for patients with relapsed/refractory AML. The only drug historically approved in this setting, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin (GO), was withdrawn from the market in 2010 due to concerns for treatment-related toxicity. Thus, there is a clear and unmet need for effective treatment options for patients with relapsed/refractory AML.
In the past decade, extraordinary progress has been made in understanding cancer biology and mechanisms of leukemogenesis. With the advent and streamlining of modern techniques such as next-generation sequencing, recurrent genomic alterations including cytogenetic abnormalities and somatic mutations can be routinely identified in over 95 percent of AML cases.
Increased knowledge of genomic abnormalities has already led to improved prognostic classification of patients with AML at diagnosis--i.e., the updated European Leukemia Net (ELN) classification system. In addition to improved AML risk-stratification, improved understanding of clonal AML architecture is leading to rationally designed treatment strategies to improve upon both the initial and salvage treatment regimens.
Treatment Options for Relapsed/Refractory AML
Relapsed/refractory AML can be (rather simplistically) divided into two groups: (1) AML that is sensitive to the conventional chemotherapeutic agents--i.e., cytarabine and anthracyclines; and (2) AML that is intrinsically resistant to or has developed secondary resistance to standard IC. Notably, there are certain AML subgroups, such as the core-binding factor leukemias (inv(16) or t(8;21)) and perhaps the newly defined ELN favorable subgroups that are exceptionally sensitive to high-dose cytarabine-based regimens; dose intensification may benefit these patients. Additionally, if a long time has elapsed between initial complete response from a conventional IC regimen before relapse (often considered > 12 months) re-challenging the patient with IC is a warranted and often successful strategy.
For patients with relapsed or refractory AML who fall into the second category, several investigational treatment approaches exist. Detailed AML characterization at the time of relapse is essential, in terms of immunohistochemistry and cytogenetic and molecular annotation, to fully consider all novel agents available on the existing clinical trials.
Avenues of Salvage Therapy/Clinical Trials:
Molecularly Targeted therapy
Identification of recurrent somatic mutations in AML has improved our understanding of AML pathophysiology, and our awareness of functional AML subsets can now be used to inform rational treatment strategies. Clinical trials with tyrosine kinase inhibitors (e.g., sorafenib, quizartinib, midostaurin, and crenolanib) for patients with activating FLT3 mutations are well underway, with demonstrable activity both as monotherapy and in combination regimens in the front-line and relapsed setting. IDH1 or IDH2 mutations are recurrently identified in about 20 percent of AML patients, with an increased incidence with increasing patient age, and targeted small molecule IDH1 and IDH2 inhibitors are now available in clinical trials with promising early efficacy as monotherapy in relapsed patients.
Somatic mutations in NRAS or KRAS are also frequent in AML patients, and combination strategies of PI3K/AKT-signaling inhibition and RAS/RAF/MEK/ERK pathway inhibition are ongoing strategies for RAS-mutated AML.
Monoclonal antibodies against commonly expressed myeloid antigens are currently under development, and can be regarded as akin to the anti-CD19, -CD20, and –CD22 antibodies available for patients with lymphoid malignancies.
While the initial anti-CD33 immunotoxin GO is no longer clinically available, novel anti-CD33 compounds including innovative bispecific T-cell engaging (BITE) therapies are now available within clinical trials. Monoclonal antibodies directed against the IL-3R (anti-CD123) are also under clinical development.
As in lymphoid neoplasms, where the addition of monoclonal antibodies to the standard cytotoxic regimens have improved outcomes significantly, it is hoped that the addition of effective antibody-based therapies to AML-specific regimens will improve the outcomes for the majority of patients with AML who express these surface antigens.
The frequency of genomic alterations leading to aberrant epigenetic regulation (i.e., mutations in IDH1/2, DNMT3A, TET2, EZH2, ASXL1, MLL, and others) supports the dysregulation of epigenetic machinery as a fundamental component of leukemogenesis. Treatment with the hypomethylating agents azacitidine and decitabine, provides an important approach in both the front-line and relapsed settings (particularly in the elderly population due to the better tolerability of these agents), with responses seen regardless of the identification of epigenetic mutations. Second-generation hypomethylating agents (SGI-110) are also under clinical development, with a randomized Phase III study ongoing.
Additional Salvage Treatment Options
An exhaustive list of currently available and promising clinical trials for patients with relapsed/refractory AML is outside the scope of this brief review, as the speed of scientific discovery in the past decade has led to the development of numerous exciting compounds with unique mechanisms of action and improved safety profiles.
Some notable compounds include the small molecule BCL2 inhibitor (venetoclax), MDM2 inhibitors, the selective inhibitor of nuclear export (SINE) compound selinexor (KPT-330), and the Polo-like kinase-1 inhibitor volasertib. Referral of patients with AML and relapsed/refractory disease to academic leukemia centers of excellence for consideration of appropriate investigational clinical trials is paramount.
We expect that the future of AML therapy will incorporate well-designed and target-specific molecules into current treatment strategies in an individualized manner, founded upon a detailed understanding of the specific genomic aberrations and aberrant signaling pathways unique to each individual patient.
With improved identification of patient-specific leukemia-promoting pathogenic processes as well as the expanding armamentarium of effective therapeutic options, we will likely witness continued progress in the management of patients with relapsed/refractory AML.
Courtney D. DiNardo, MD, MSCE, is Assistant Professor of Medicine in the Department of Leukemia at the University of Texas MD Anderson Cancer Center; and Farhad Ravandi, MD, is Professor of Medicine and Chief of the Section of Developmental Therapeutics in the Department of Leukemia at the University of Texas MD Anderson Cancer Center.
Friday, May 29, 2015
BY RICHARD GORLICK, MD
Professor of Pediatrics and Molecular Pharmacology,
The Albert Einstein College of Medicine of Yeshiva University;
Vice Chairman of Pediatrics and Division Chief of Pediatric Hematology, Oncology and Marrow and Blood Cell Transplantation, The Children’s Hospital at Montefiore, Bronx, NY
All cancers in children and young adults are fortunately rare. Even in their period of most frequent incidence, during the second decade of life, bone tumors are not the most common malignancy of childhood. For sarcoma oncologists, most patients referred to your practice have a high enough probability of having cancer that everyone can be more thoroughly assessed, which is not the case for primary care providers.
It can be very challenging for the pediatrician and orthopedic surgeons to consider a bone cancer as a possible diagnosis in the myriad patients who present complaining of pain or a mass more often resulting from benign etiologies. Trauma, growing pains, and osteomyelitis are all more common than bone cancer.
The advice given to primary care providers is that in patients with persistence of pain or the association of the pain with a mass, particularly when symptoms are becoming more severe over time, further evaluation with a plain radiograph of the site is warranted.
The two most common bone cancers in younger patients are osteosarcoma and Ewing sarcoma family tumors, with approximately 400 and 200 new pediatric cases per year, respectively, in North America. Although they can occur in any bone in the body, approximately half of osteosarcomas occur in the region around the knee. The majority of Ewing sarcoma family tumors occur in the appendicular skeleton even though this entity’s tropism away from the axial skeleton is not as pronounced as for osteosarcoma. This, coupled with the age distribution of these cancers, dictates a higher level of concern for malignancy in teenagers with symptoms and physical exam findings around their knees.
Once a plain radiograph is obtained, bone tumors usually have a dramatic appearance, and a completely negative radiograph is reassuring that a cancer is not present. Osteosarcomas often have soft tissue extension with a periosteal reaction that is classically described as having a “sun-burst” appearance in the metaphyseal region of the bone.
Ewing sarcoma family tumors are permeative, leading to a periosteal reaction that is lamellar or “onion skinning” in appearance in the diaphyseal or metaphyseal region of bones. Occasionally patients with bone cancer will present more dramatically with pathological fractures, but even in some of these cases, a reported history of trauma may muddy the picture, leading to confusion and misdiagnosis, so a high index of suspicion always needs to be maintained to avoid delays in diagnosis.
Once a diagnosis of a bone cancer is suspected prompt referral to a group with expertise in sarcomas is strongly recommended as these patients require complex multidisciplinary care.
Multidisciplinary Sarcoma Care
All bone cancers require multidisciplinary care by physicians with expertise in their management. For this purpose, all new patients seen at our sarcoma center are seen right from the first encounter by both a pediatric/medical oncologist and an orthopedic oncologist, at the same time, in shared clinic space.
A history and physical examination along with plain radiographs dictates further evaluation. One needs to consider the benign entities that can mimic more aggressive lesions as well as variant osteosarcoma and Ewing sarcoma family tumor appearances, which can misleadingly suggest a benign lesion.
In most patients at least additional imaging is warranted, which is typically magnetic resonance imaging of the site, with and without gadolinium contrast including the entire bone to capture skip lesions that may be present. This is best done prior to the biopsy to assist in decision making and biopsy placement and so that the appearance of the lesion prior to its disruption by the biopsy can be appreciated.
In patients strongly suspected of having osteosarcoma or a Ewing sarcoma family tumor, high-resolution chest computed tomography is obtained prior to biopsy to avoid issues of postoperative atelectasis creating challenges in interpretation of findings within the lungs, as this is the site in which metastases are most likely to occur.
In all patients being biopsied at least a chest radiograph is warranted. Elevated alkaline phosphatase and lactate dehydrogenase supports a probable diagnosis of a bone cancer.
I am a strong advocate of open biopsies, but many institutions have core needle biopsies performed by interventional radiologists or orthopedic surgeons with this topic being immensely controversial.
Universally endorsed is the belief that the biopsy needs to be performed by someone with experience in resecting bone cancer, with the critical issue being consideration of the surgical plan for definitive resection. If the pathology reveals a cancer of bone, the needle, or incision tract will need to be removed along with the tumor en block, to abrogate the risk of seeding the site with tumor cells.
Osteosarcoma is diagnosed by a bone tumor pathologist based on the histologic appearance of a malignant spindle cell tumor that produces osteoid. Ewing sarcoma family tumors are small round blue cell tumors which typically express CD99 and possess one of a number of recurrent chromosomal translocations most commonly involving the EWS and FLI genes on chromosomes 11 and 22 detected via FISH or PCR and are disease defining.
Once the diagnosis is made, the staging workup is completed with a technetium bone scan, and additionally, in the case of Ewing sarcoma family tumors multiple site bone marrow aspirates and biopsies.
The role of PET scans in routine clinical practice for bone sarcomas remains undefined. A central venous catheter is required for the types of systemic chemotherapy that are typically utilized, and additional pre-treatment assessments of organ function are performed appropriate to the planned treatment. Fertility preservation methods need to be discussed with all patients.
Systemic and Local Therapy
The standard of care for all patients with high-grade osteosarcoma and Ewing sarcoma family tumors is the use of neoadjuvant chemotherapy, followed by local control and subsequently additional adjuvant chemotherapy. Systemic therapy is needed because of the high frequency of micro-metastases in patients with radiographically localized disease.
Routine clinical practice for younger patients with bone cancers is heavily dictated by Children’s Oncology Group clinical trials. If a Phase III trial is active for newly diagnosed patients offering participation is routine. In the absence of a front-line study the superior arm of the last Phase III trial is used typically as standard therapy.
For osteosarcoma patients, front-line studies are not active at present, with the standard arm of the last international Phase III study, the EURAMOS study, being superior to the experimental arms. As such, the standard induction and adjuvant chemotherapy is comprised of cisplatin and doxorubicin alternating with two consecutive weeks of high-dose methotrexate in accordance with the schema in the EURAMOS study.
Local control requires a complete surgical resection of the tumor as osteosarcoma is relatively radiation resistant. These resections typically do not require amputation, and considerable advances have been made in the surgery as well as the typically metallic internal prostheses yielding numerous functional enhancements.
The field of orthopedic oncology is highly specialized, interesting, and beyond the scope of the present discussion. The degree of necrosis in the resected tumor samples is prognostic but thus far has been shown to be of no clinical value for tailoring subsequent therapy. In patients with osteosarcoma and pulmonary metastases the nodules need to be resected. In our institution this is performed as bilateral staged thoracotomies but considerable variation in practice exists.
For patients with newly diagnosed Ewing sarcoma family tumors, active Children’s Oncology Group clinical trials are ongoing. All patients are given intensively timed cyclophosphamide, doxorubicin, and vincristine alternating with ifosfamide and etoposide as this resulted in superior survival in the last Phase III trial and represents the standard of care.
In patients with localized disease the randomized question is whether the addition of cyclophosphamide, topotecan, and vincristine improves survival. In patients presenting with metastatic disease the randomized question is whether the addition of ganitumab, an antibody to IGF-1R, improves survival. Local control is performed after neoadjuvant chemotherapy but, unlike osteosarcoma, can involve either surgery or radiation therapy or both. Whether a patient receives surgery or radiation therapy frequently is decided based on the functional consequences and late effects of each. Considerable variation exists in institutional practice. In patients with metastatic disease radiation therapy is more frequently utilized.
Care of Patients with Recurrent Osteosarcoma and Ewing Sarcoma
Approximately 60 to 70 percent of patients presenting with localized high-grade osteosarcoma or Ewing sarcoma family tumors will have long-term disease-free survival with the aforementioned therapy. For the 20 percent of patients who present with radiographically visible metastatic disease, the prognosis is markedly worse and further influenced by the extent of the metastatic disease. Similarly the prognosis of patients with recurrent disease is poor.
In patients with recurrent osteosarcoma, metastectomy has been shown to be of clinical benefit with a small percentage of patients having durable disease-free survival with resection alone. The value of salvage chemotherapy, typically ifosfamide and etoposide is controversial. In Ewing sarcoma family tumors radiation therapy is employed for local control with cyclophosphamide, topotecan, and vincristine or temozolomide, irinotecan, and vincristine being the most typical salvage therapies.
Numerous clinical trials of novel agents are being performed in patients with recurrent osteosarcoma and Ewing sarcoma family tumors, and participation in these trials can be offered. It is hoped that some of these ever-changing menu of agents will prove effective in the therapy of patients with recurrent bone cancer, and will improve survival when added to upfront therapy of newly diagnosed patients, which will need to be proven in the context of future randomized Phase III trials.
Tuesday, February 24, 2015
BY Sandy Srinivas, MD
Associate Professor of Medicine (Oncology)
Stanford University Medical Center
Prostate cancer spans a spectrum like all cancers, ranging from localized disease to metastatic disease. As with breast cancer, prostate cancer is exquisitely sensitive to hormonal manipulation, and from a practical point of view is divided into hormone-naïve versus castrate-resistant disease.
Recurrent Prostate Cancer Post-localized Disease
Recurrent post-localized prostate cancer is usually manifested by a climbing serum prostate-specific antigen (PSA) after therapy for localized disease. Typically, I stage patients with a CT scan and bone imaging, either with a bone scan or a F18 PET scan. When PSA doubling time (PSA DT) becomes less than six months, androgen-deprivation therapy (ADT) is initiated.
In general, if scans show no metastases, I start patients on LHRH analogs such as leuprolide or gosserlin. There are LHRH antagonists commercially available that can be used as well. I tend to offer patients intermittent ADT as long as patients appear to be reliable and motivated for follow-ups.
I do not use a specific PSA level to reinitiate therapy but rather look at the rate at which the PSA rises. Every time it takes a sharp rise, I tend to reimage, and do not do scans on a set schedule.
Metastatic Prostate Cancer
Due to the current controversies about PSA screening, we are seeing more patients with newly diagnosed metastatic prostate cancer now than five years ago. Based on the CHARTERED trial, which showed a significant survival advantage to the use of chemotherapy along with ADT, I do offer docetaxel x 6 cycles in addition to ADT for these patients with bone or visceral metastases.
For patients with recurrent prostate cancer following localized disease, I start them on ADT. I offer intermittent ADT even in patients with metastatic disease after having a discussion with patients regarding their goals and tolerability to ADT.
Ultimately, castrate resistance--defined as a rising serum PSA despite low testosterone--develops in almost all patients starting ADT. I will reimage them to set a new baseline, and if the patient remains non-metastatic, I would use drugs such as bicalutamide first. In general responses are variable, and if serum PSA rises, I will initiate anti-androgen withdrawal and then reimage again. If patients are non-metastatic, I would pursue older drugs such as nilutamide or even ketoconazole/hydrocortisone--surveillance alone may also be appropriate in certain cases.
Metastatic Castrate-Resistant Prostate Cancer
Management of patients with metastatic castrate-resistant prostate cancer has become challenging, as there are several FDA-approved drugs for this group of patients. These include sipuleucel-T, abiraterone, enzlautamide, radium 223, as well as chemotherapy. I use Provenge or sipuleucel-T when patients have slow-rising PSA with long PSA DT and when they are asymptomatic and not too concerned about PSA values.
I use enzalutamide if patients have issues with diabetes or poorly controlled hypertension and abiraterone with prednisone if they have pain and would benefit from the prednisone use. Typically I do not use these drugs back to back, as there is a very low chance of response.
After failure of either enzalutamide or abiraterone, I re-scan. If patients have bone-only disease, I would recommend alpharadin (radium-223, Xofigo) for six cycles. If patients have bulky nodal disease or visceral disease, I would recommend chemotherapy with docetaxel.
I typically stop chemotherapy after six to eight cycles and give patients a chemotherapy holiday. I will treat with additional hormonal agents such as abiraterone or enzalutamide if patients have never received that drug. For patients progressing after this, I will re-treat with docetaxel if it has been more than a year since the last treatment; otherwise I recommend cabazitaxel.
While mitoxantrone is an old drug, I still use it in patients who have progressed on taxanes or those who have had an allergic reaction to taxanes.
Bone health is a vital part of the care of patients with prostate cancer. I use bone-modifying drugs in patients with castrate metastatic prostate cancer but not in those with newly diagnosed bone metastases. A randomized trial from CALGB did not support the use of zoledronic acid in newly diagnosed metastatic prostate cancer patients. I will use zoledronic acid or denosumab every three months along with a GNRH analog, which I continue as well.