Naval Daver

Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation

Patients received 5-azacytidine (AZA) 75 mg/m(2) intravenously daily for 7 days and sorafenib 400 mg orally twice daily continuously; cycles were repeated at ~1-month intervals. Forty-three acute myeloid leukemia (AML) patients with a median age of 64 years (range, 24-87 years) were enrolled; 37 were evaluable for response. FMS-like tyrosine kinase-3 (FLT3)-internal tandem duplication (ITD) mutation was detected in 40 (93%) patients, with a median allelic ratio of 0.32 (range, 0.009-0.93). They had received a median of 2 prior treatment regimens (range, 0-7); 9 had failed prior therapy with a FLT3 kinase inhibitor. The response rate was 46%, including 10 (27%) complete response with incomplete count recovery (CRi), 6 (16%) complete responses (CR), and 1 (3%) partial response. The median time to achieve CR/CRi was 2 cycles (range, 1-4), and the median duration of CR/CRi was 2.3 months (range, 1-14.3 months). Sixty-four percent of patients achieved adequate (defined as >85%) FLT3 inhibition during their first cycle of therapy. The degree of FLT3 inhibition correlated with plasma sorafenib concentrations. FLT3 ligand levels did not rise to levels seen in prior studies of patients receiving cytotoxic chemotherapy. The combination of AZA and sorafenib is effective for patients with relapsed AML and FLT-3-ITD. This trial was registered at clinicaltrials.gov as #NCT01254890.

Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study

BACKGROUND Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. METHODS In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312. FINDINGS Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 [41%] of 93 patients), pneumonia (27 [29%] of 93 patients), thrombocytopenia (23 [25%] of 93 patients), anaemia (23 [25%] of 93 patients), and sepsis (16 [17%] of 93 patients). The most common serious adverse events were febrile neutropenia (29 [31%] of 93 patients), pneumonia (26 [28%] of 93 patients), and sepsis (16 [17%] of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m(2) daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m(2) daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m(2) (designated as the biologically effective dose). INTERPRETATION Guadecitabine given subcutaneously at 60 mg/m(2) daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m(2) daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies. FUNDING Astex Pharmaceuticals, Stand Up To Cancer.

Chimeric antigen receptor T-cell therapy — assessment and management of toxicities

Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and non-haematological malignancies. CAR-T-cell therapy can induce rapid and durable clinical responses, but is associated with unique acute toxicities, which can be severe or even fatal. Cytokine-release syndrome (CRS), the most commonly observed toxicity, can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan dysfunction; rarely, severe CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH). Neurotoxicity, termed CAR-T-cell-related encephalopathy syndrome (CRES), is the second most-common adverse event, and can occur concurrently with or after CRS. Intensive monitoring and prompt management of toxicities is essential to minimize the morbidity and mortality associated with this potentially curative therapeutic approach; however, algorithms for accurate and consistent grading and management of the toxicities are lacking. To address this unmet need, we formed a CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising investigators from multiple institutions and medical disciplines who have experience in treating patients with various CAR-T-cell therapy products. Herein, we describe the multidisciplinary approach adopted at our institutions, and provide recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy.

Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: analysis of patient data from six prospective clinical trials

Summary Background Tyrosine kinase inhibitors (TKIs) improved overall survival (OS) in patients with chronic myeloid leukemia in chronic phase (CML-CP). The purpose of this study was to compare OS in patients with newly diagnosed CML-CP to that of general population. Methods Response and survival data in six consecutive or parallel prospective clinical TKI trials were analyzed. Estimated OS rates in the general population matched by age, gender, ethnicity, and year at diagnosis were obtained from national vital statistics reports. Survival was also assessed by response and type of TKI. Findings Of the 483 patients, 271 patients received imatinib, 105 nilotinib and 107 dasatinib. The age grouping was as follows: 15–44 years, 197 patients; 45–64 years, 222; 65–84 years, 64. Five-year OS in CML-CP decreased with increasing age: 15–44 years, 96% (95% confidence interval[CI], 93·2–99·2); 45–64 years, 94% (95%CI, 89·9–97·1); and 65–84 years, 80% (95%CI, 69·5–90·7). Five-year relative OS was only slightly lower compared to the matched general population: 15–44 years, 97% (95%CI, 94·0–100·0); 45–64 years, 97% (95%CI, 92·9–100·3); and 65–84 years, 92% (95%CI, 79·5–103·8). Five-year relative OS in all ages with complete cytogenetic response (CCyR) or better was similar to that in the general population. Interpretation With TKI, the expected survival of patients diagnosed with CML-CP is only slightly lower to that of the general population, and for those patients who achieved CCyR or better it is similar to that of general population. Due to the relatively smaller number of patients followed for 10 years and the small number of older patients, the 10-year relative OS has a wider confidence interval and might vary with longer follow-up. However, 10-year relative OS derived from the imatinib cohort is favorable, and, considering the overall better results with dasatinib and nilotinib, it is reasonable to expect that the results will remain at least as favorable with additional follow-up observation with dasatinib or nilotinib. Thus with access to TKI, it is possible that most patients with CML can enjoy a near normal life expectancy.BACKGROUND Tyrosine-kinase inhibitors improve overall survival in patients with chronic myeloid leukaemia in chronic phase (CML-CP). Survival compared with the general population by age, response, and type of tyrosine-kinase inhibitor is not known. With use of data from trials of tyrosine kinase inhibitors, we compared overall survival in patients with newly diagnosed CML-CP to that of general population. METHODS In this cohort analysis, we included data from patients with CML-CP enrolled in six consecutive or parallel prospective clinical trials of tyrosine-kinase inhibitors at a single institution from July 30, 2000, to Sept 17, 2012. We analysed data for response and survival with the Kaplan-Meier method. For estimated overall survival in the general population, we obtained data from national vital statistics reports and matched to patients with CML-CP by age, sex, ethnicity, and year at diagnosis. We assessed numbers and causes of death within 1 year of beginning treatment by age group and by response to therapy. We then did univariate analysis and multivariate analysis to investigate factors associated with survival probability. FINDINGS Our analysis included 483 patients, 271 received imatinib, 105 received nilotinib, and 107 received dasatinib. Most patients were younger than 65 years, and no patients were older than 85 years. Median follow-up was 99·4 months (IQR 44·9-121·6), by which time 53 (11%) patients had died. The most common causes of death were progression to advanced disease stage, including complications of stem-cell transplantation (17 [4%] patients), secondary malignancies (nine [2%] patients), and cardiovascular causes (nine [2%] patients). 5-year overall survival in patients with CML-CP decreased in older age categories. For the whole population of patients with CML-CP, 5-year survival was only slightly lower than that of the matched general population (relative survival 94·7% [95% 92·1-97·4]). Individuals of all ages with a report of complete cytogenetic response to treatment or deeper within 1 year had a 5-year survival similar to that of the general population. INTERPRETATION In the era of treatment with tyrosine-kinase inhibitors, patients diagnosed with CML-CP can expect a 5-year survival that is only slightly lower than that of the general population. With access to tyrosine-kinase inhibitors, most patients with chronic myeloid leukaemia could enjoy a near normal life expectancy. FUNDING MD Anderson Cancer Center, National Cancer Institute.

Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic Leukemia

We have previously reported on the efficacy and tolerability of hyper-CVAD regimen (cyclophosphamide, vincristine, Adriamycin, and dexamethasone) and imatinib followed by imatinib-based consolidation/maintenance therapy in 20 patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Here, we present the 13-year follow up of our study. Fifty-four patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia were enrolled: 39 (72%) with de novo disease, 6 (11%) whose disease was primary refractory after induction (without a tyrosine kinase inhibitor), and 9 (17%) in complete remission after one course of induction therapy (without tyrosine kinase inhibitor). Forty-two (93%) of the 45 patients treated for active disease achieved complete remission, one achieved complete remission with incomplete recovery of platelets, one achieved partial remission and one died during induction. Nineteen (35%) patients are alive and 18 are in complete remission. The 5-year overall survival rate for all patients was 43%. Significant negative predictors of overall survival were age over 60 years, p190 molecular transcript, and active disease at enrollment. Sixteen (30%) patients underwent allogeneic stem cell transplantation. Median overall survival was not significantly greater for patients who underwent transplant. Patients with residual molecular disease at three months had improved complete remission duration with transplant. The median time to hematologic recovery and severe toxicities with combination were not significantly different from those observed with conventional chemotherapy. Only one patient discontinued therapy due to toxicity. HyperCVAD chemotherapy and imatinib is an effective regimen for Philadelphia-positive acute lymphoblastic leukemia. Transplant may not be indicated in all patients with Philadelphia-positive acute lymphoblastic leukemia. (clinicaltrials.gov identifier: NCT00038610)

Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome

We investigated the combination of midostaurin and azacitidine (AZA) in patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). Patients received AZA 75 mg m−2 on days 1–7 and midostaurin 25 mg bid (in cohort 1 of phase I) or 50 mg bid (in cohort 2 of Phase I and in Phase II) orally on day 8–21 during the first cycle and continuously thereafter. Fourteen patients were enrolled in the phase I and 40 in the phase II. Overall response rate was 26%. The median remission duration (RD) was 20 weeks and was significantly longer in patients with FLT3 mutations not previously exposed to other FLT3 inhibitors (P = 0.05) and in patients not previously transplanted (P = 0.01). Thirty‐two (59%) patients have died, all of complications related to disease progression. G3‐4 nonhematological toxicity was reported in 38 (70%) patients, most frequently infections (56%), ejection fraction reduction (11%), and diarrhea or nausea/vomiting (9% each). The combination of midostaurin and AZA is an effective and safe regimen in patients with AML and high‐risk MDS. Patients with FLT3 mutations but not previously exposed to other FLT3 inhibitors and patients not previously transplanted derived the greatest benefit. Further studies with this combination are warranted. Am. J. Hematol. 90:276–281, 2015.

Phase 1 study of an anti-CD33 immunotoxin, humanized monoclonal antibody M195 conjugated to recombinant gelonin (HUM-195/rGEL), in patients with advanced myeloid malignancies

We conducted a phase 1 study of an anti-CD33 immunotoxin, humanized monoclonal antibody M195 conjugated to recombinant gelonin (HUM-195/rGEL), in patients with relapsed, refractory myeloid leukemias. Twenty-eight patients received the construct intravenously at four dose levels (12, 18, 28 and 40 mg/m2 per course) in a “3+3” study design. The dose-limiting toxicity was infusion-related allergic reaction including hypoxia and hypotension. The 28 mg/m2 total dose was considered the maximally tolerated dose. Four patients developed a reduction in peripheral blood blasts of at least 50%. Three patients treated with the 10, 12 and 28 mg/m2 doses showed a 38-50% reduction in bone marrow blasts. There was normalization of platelets in one patient treated with 40 mg/m2. Pharmacokinetic analysis demonstrated that the highest blood levels achieved were 200-300 ng/mL which cleared with a half-life of ∼20 hours. Antigenicity was low with one patient at the 12 mg/m2 dose and one patient at the 18 mg/m2 dose (2/23, <10%) developing antibodies to the recombinant gelonin component after 28 days. We concluded that HUM-195/rGel can be safely administered in a multi-dose cycle to patients with advanced myeloid malignancies and warrants further investigation.

Secondary mutations as mediators of resistance to targeted therapy in leukemia.

The advent of small molecule-based targeted therapy has improved the treatment of both acute and chronic leukemias. Resistance to small molecule inhibitors has emerged as a common theme. The most frequent mode of acquired resistance is the acquisition of point mutations in the kinase domain. FLT3 inhibitors have improved response rates in FLT3-mutated acute myeloid leukemia (AML). The occurrence of the ATP-binding site and activation loop mutations confers varying degrees of resistance to the individual FLT3 inhibitors. Second-generation FLT3 inhibitors such as crenolanib may overcome the resistance of these mutations. Furthermore, nonmutational mechanisms of resistance such as prosurvival pathways and bone marrow signaling may be upregulated in FLT3 inhibitor-resistant AML with secondary kinase domain mutations. More recently, point mutations conferring resistance to the Bruton tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia, arsenic trioxide in acute promyelocytic leukemia, and the BH3-mimetic ABT199 in lymphoma have been identified. In chronic myeloid leukemia, the emergence of tyrosine kinase domain mutations has historically been the dominant mechanism of resistance. The early identification of secondary point mutations and their downstream effects along with the development of second- or third-generation inhibitors and rationally designed small molecule combinations are potential strategies to overcome mutation-mediated resistance.

Augmented Berlin-Frankfurt-Münster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL).

Various trials have reported improved outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) who received treatment with pediatric‐based regimens. Those reports prompted the current investigation of the pediatric augmented Berlin‐Frankfurt‐Münster (ABFM) regimen in AYA patients. The results were compared with those from a similar population that received the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper‐CVAD) regimen.

Ponatinib as first-line treatment for patients with chronic myeloid leukaemia in chronic phase: a phase 2 study

BACKGROUND Ponatinib has shown efficacy in patients with refractory chronic myeloid leukaemia (CML) and in those with CML with a Thr315Ile mutation. We aimed to investigate the activity and safety of ponatinib as first-line treatment for patients with chronic-phase CML. METHODS We did a single-arm, phase 2 trial at MD Anderson Cancer Center in Houston, TX, USA. Between May 3, 2012, and Sept 24, 2013, we enrolled patients with early (<6 months) chronic-phase CML and treated them with oral ponatinib once a day. Patients enrolled before July 25, 2013, were given a starting dose of 45 mg per day; we lowered this due to tolerability issues and patients enrolled after this date were given a starting dose of 30 mg per day. After a warning by the US Food and Drug Administration (FDA) in Oct 6, 2013, for vascular complications with ponatinib, we started all patients on aspirin 81 mg daily and reduced the dose of ponatinib to 30 mg or 15 mg per day for all patients. The primary endpoint was the proportion of patients who achieved complete cytogenetic response by 6 months in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01570868. FINDINGS We enrolled 51 patients. Median follow-up was 20·9 months (IQR 14·9–25·2). 43 patients were started on 45 mg ponatinib every day; eight patients were started on 30 mg per day. 43 (94%) of 46 evaluable patients achieved complete cytogenetic response at 6 months. Most frequent toxicities included skin-related effects (n=35; 69%) and elevated lipase (n=32; 63%). Cardiovascular events (mainly hypertension) occurred in 25 (49%) patients. Grade 3–4 myelosuppression occurred in 15 (29%) patients. Five (10%) patients developed cerebrovascular or vaso-occlusive disease. 43 (85%) patients needed treatment interruptions at some time and 45 (88%) needed dose reductions. The study was terminated June 18, 2014, at the recommendation of the FDA due to concern about the increased risk of thromboembolism with ponatinib. INTERPRETATION Patients with newly diagnosed CML in chronic phase respond well to treatment with ponatinib, with most achieving a complete cytogenetic response. Dose adjustment, extensive monitoring, and counselling of the patients for thromboembolic events is needed for patients on ponatinib therapy. However, due to the risk of vascular thrombotic events and the availability of alternative options for these patients, other drugs should be considered first in the frontline setting. FUNDING MD Anderson Cancer Center, National Cancer Institute, ARIAD Pharmaceutical.