Deborah A. Thomas

Early Results of a Chemoimmunotherapy Regimen of Fludarabine, Cyclophosphamide, and Rituximab As Initial Therapy for Chronic Lymphocytic Leukemia

PURPOSE Fludarabine and cyclophosphamide (FC), which are active in treatment of chronic lymphocytic leukemia (CLL), are synergistic with the monoclonal antibody rituximab in vitro in lymphoma cell lines. A chemoimmunotherapy program consisting of fludarabine, cyclophosphamide, and rituximab (FCR) was developed with the goal of increasing the complete remission (CR) rate in previously untreated CLL patients to >/= 50%. PATIENTS AND METHODS We conducted a single-arm study of FCR as initial therapy in 224 patients with progressive or advanced CLL. Flow cytometry was used to measure residual disease. Results and safety were compared with a previous regimen using FC. RESULTS The median age was 58 years; 75 patients (33%) had Rai stage III to IV disease. The CR rate was 70% (95% CI, 63% to 76%), the nodular partial remission rate was 10%, and the partial remission rate was 15%, for an overall response rate of 95% (95% CI, 92% to 98%). Two thirds of patients evaluated with flow cytometry had less than 1% CD5- and CD19-coexpressing cells in bone marrow after therapy. Grade 3 to 4 neutropenia occurred during 52% of courses; major and minor infections were seen in 2.6% and 10% of courses, respectively. One third of the 224 patients had >/= one episode of infection, and 10% had a fever of unknown origin. CONCLUSION FCR produced a high CR rate in previously untreated CLL. Most patients had no detectable disease on flow cytometry at the end of therapy. Time to treatment failure analysis showed that 69% of patients were projected to be failure free at 4 years (95% CI, 57% to 81%).

Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis

BACKGROUND Myelofibrosis is a Philadelphia chromosome–negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor. METHODS We conducted a phase 1−2 trial of INCB018424 in patients with JAK2 V617F−positive or JAK2 V617F−negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis. RESULTS A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis. CONCLUSIONS INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed. (Funded by Incyte; ClinicalTrials.gov number, NCT00509899.)

Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia

Early results of the fludarabine, cyclophosphamide, and rituximab (FCR) regimen in 224 patients showed that it was highly active as initial therapy of chronic lymphocytic leukemia. In this report, we present the final results of all 300 study patients at a median follow up of 6 years. The overall response rate was 95%, with complete remission in 72%, nodular partial remission in 10%, partial remission due to cytopenia in 7%, and partial remission due to residual disease in 6%. Two patients (< 1%) died within 3 months of starting therapy. Six-year overall and failure-free survival were 77% and 51%, respectively. Median time to progression was 80 months. Pretreatment characteristics independently associated with inferior response were age 70 years or older, beta2-microglobulin twice the upper limit of normal (2N) or more, white cell count 150 x 10(9)/L or more, abnormal chromosome 17, and lactate dehydrogenase 2N or more. No pretreatment characteristic was independently associated with decreased complete remission duration. The risk of late infection was 10% and 4% for the first and second years of remission, respectively, and less than 1.5% per year for the third year onward. In a multivariate analysis of patients receiving fludarabine-based therapy at our center, FCR therapy emerged as the strongest independent determinant of survival.

Rituximab dose-escalation trial in chronic lymphocytic leukemia

PURPOSE To conduct a dose-escalation trial of rituximab in patients with chronic lymphocytic leukemia (CLL) to define the maximum-tolerated dose (MTD), to evaluate first-dose reactions in patients with high circulating lymphocyte counts, and to assess the efficacy at higher versus lower doses. PATIENTS AND METHODS Fifty patients with CLL (n = 40) or other mature B-cell lymphoid leukemias (n = 10) were treated with four weekly infusions of rituximab. The first dose was 375 mg/m(2) for all patients; dose- escalation began with dose 2 but was held constant for each patient. Escalated doses were from 500 to 2,250 mg/m(2). RESULTS Toxicity with the first dose (375 mg/m(2)) was noted in 94% of patients but was grade 1 or 2 in most, predominantly fever and chills. Six patients (12%) experienced severe toxicity with the first dose, including fever, chills, dyspnea, and hypoxia in all six patients, hypotension in five, and hypertension in one. Toxicity on subsequent doses was minimal until a dose of 2,250 mg/m(2) was achieved. Eight (67%) of 12 patients had grade 2 toxicity, including fever, chills, nausea, and malaise, although no patient had grade 3 or 4 toxicity. Severe toxicity with the first dose was significantly more common in patients with other B-cell leukemias, occurring in five (50%) of 10 patients versus one (2%) of 40 patients with CLL (P <.001). The overall response rate was 40%; all responses in patients with CLL were partial remissions. Response rates were 36% in CLL and 60% in other B-cell lymphoid leukemias. Response was correlated with dose: 22% for patients treated at 500 to 825 mg/m(2), 43% for those treated at 1,000 to 1,500 mg/m(2), and 75% for those treated at the highest dose of 2,250 mg/m(2) (P =.007). The median time to disease progression was 8 months. Myelosuppression and infections were uncommon. CONCLUSION Rituximab has significant activity in patients with CLL at the higher dose levels. Severe first-dose reactions were uncommon in patients with CLL, even with high circulating lymphocyte counts, but were frequent in patients with other mature B-cell leukemias in which CD20 surface expression is increased. Efficacy of rituximab was also significant in this group of patients.

Chemoimmunotherapy With Fludarabine, Cyclophosphamide, and Rituximab for Relapsed and Refractory Chronic Lymphocytic Leukemia

PURPOSE The efficacy, toxicity, and tolerability of chemoimmunotherapy with the combination of fludarabine, cyclophosphamide, and rituximab (FCR) were evaluated in previously treated patients with chronic lymphocytic leukemia (CLL). The purpose of this study was to improve the complete remission (CR) rate for previously treated patients and evaluate the quality of bone marrow response. PATIENTS AND METHODS One hundred seventy-seven previously treated patients with CLL were evaluated. Treatment consisted of rituximab 375 mg/m(2) day 1 of course 1 and 500 mg/m(2) day 1 of courses 2 to 6; fludarabine 25 mg/m(2)/d days 2 to 4 of course 1 and days 1 to 3 of courses 2 to 6; and cyclophosphamide 250 mg/m(2)/d days 2 to 4 of course 1 and days 1 to 3 of courses 2 to 6. Courses were repeated every 4 weeks. RESULTS CR was achieved in 25% of 177 patients, and nodular partial remission and partial remission were achieved in 16% and 32% of patients, respectively; the overall response rate was 73%. Twelve (32%) of 37 complete responders tested achieved molecular remission in bone marrow. Univariate and multivariate analyses were used to identify pretreatment patient characteristics associated with CR and overall remission, longer time to progression, and overall survival. CONCLUSION The FCR regimen was an active and well-tolerated treatment for previously treated patients with CLL. Myelosuppression was the most common toxicity. FCR induced the highest CR rate reported in a clinical trial of previously treated patients with CLL. Furthermore, molecular remissions were achieved in a third of patients achieving CR.

Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia

Adult Burkitt‐type lymphoma (BL) and acute lymphoblastic leukemia (B‐ALL) are rare entities composing 1% to 5% of non‐Hodgkin lymphomas NHL) or ALL. Prognosis of BL and B‐ALL has been poor with conventional NHL or ALL regimens, but has improved with dose‐intensive regimens.

Long‐term follow‐up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper‐CVAD), a dose‐intensive regimen, in adult acute lymphocytic leukemia

Modern intensive chemotherapy regimens have improved the prognosis for patients with adult acute lymphocytic leukemia (ALL). With these regimens, the complete response rates are now reported to be > 80%, and the long‐term survival rates range from 30% to 45%. The current analysis updated the long‐term results with the original hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper‐CVAD) program, with a median follow‐up time of 63 months.

Phase I/II Study of Combination Therapy With Sorafenib, Idarubicin, and Cytarabine in Younger Patients With Acute Myeloid Leukemia

PURPOSE To determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years. PATIENTS AND METHODS In the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m(2) by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m(2) IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days. RESULTS Overall, 38 (75%) patients have achieved a complete remission (CR), including 14 (93%) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66%) of 36 patients with FLT3 wild-type (WT) disease (three additional FLT3-WT patients had CRp). FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients (P = .033). With a median follow-up of 54 weeks (range, 8 to 87 weeks), the probability of survival at 1 year is 74%. Among the FLT3-mutated patients, 10 have relapsed and five remain in CR with a median follow-up of 62 weeks (range, 10 to 76 weeks). Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity. CONCLUSION Sorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling.

Phase I/II Study of the Mammalian Target of Rapamycin Inhibitor Everolimus (RAD001) in Patients with Relapsed or Refractory Hematologic Malignancies

Purpose: Everolimus (RAD001, Novartis), an oral derivative of rapamycin, inhibits the mammalian target of rapamycin (mTOR), which regulates many aspects of cell growth and division. A phase I/II study was done to determine safety and efficacy of everolimus in patients with relapsed or refractory hematologic malignancies. Experimental Design: Two dose levels (5 and 10 mg orally once daily continuously) were evaluated in the phase I portion of this study to determine the maximum tolerated dose of everolimus to be used in the phase II study. Results: Twenty-seven patients (9 acute myelogenous leukemia, 5 myelodysplastic syndrome, 6 B-chronic lymphocytic leukemia, 4 mantle cell lymphoma, 1 myelofibrosis, 1 natural killer cell/T-cell leukemia, and 1 T-cell prolymphocytic leukemia) received everolimus. No dose-limiting toxicities were observed. Grade 3 potentially drug-related toxicities included hyperglycemia (22%), hypophosphatemia (7%), fatigue (7%), anorexia (4%), and diarrhea (4%). One patient developed a cutaneous leukocytoclastic vasculitis requiring a skin graft. One patient with refractory anemia with excess blasts achieved a major platelet response of over 3-month duration. A second patient with refractory anemia with excess blasts showed a minor platelet response of 25-day duration. Phosphorylation of downstream targets of mTOR, eukaryotic initiation factor 4E-binding protein 1, and/or, p70 S6 kinase, was inhibited in six of nine patient samples, including those from the patient with a major platelet response. Conclusions: Everolimus is well tolerated at a daily dose of 10 mg daily and may have activity in patients with myelodysplastic syndrome. Studies of everolimus in combination with therapeutic agents directed against other components of the phosphatidylinositol 3-kinase/Akt/mTOR pathway are warranted.

Inotuzumab ozogamicin, an anti-CD22–calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study

BACKGROUND The outlook for patients with refractory and relapsed acute lymphocytic leukaemia (ALL) is poor. CD22 is highly expressed in patients with ALL. Inotuzumab ozogamicin is a CD22 monoclonal antibody conjugated to the toxin calecheamicin. We did a phase 2 study to assess the efficacy of this antibody. METHODS We recruited patients at the MD Anderson Cancer Center, Houston, TX, USA, between June, 2010, and March, 2011. Adults and children with refractory and relapsed ALL were eligible. Ten adults were treated before enrolment of children started. Patients were given 1·8 mg/m(2) inotuzumab ozogamicin intravenously over 1 h every 3-4 weeks (the first three adults and three children received 1·3 mg/m(2) in the first course). The primary endpoint was overall response (complete response or marrow complete response with no recovery of platelet count or incomplete recovery of neutrophil and platelet counts). Analysis was done by intention to treat. This study is registered, number NCT01134575. FINDINGS 49 patients were enrolled and treated. Median age was 36 years (range 6-80). CD22 was expressed in more than 50% of blasts in all patients. The median number of courses was two (range one to five) and the median time between courses was 3 weeks (range 3-6). Nine (18%) patients had complete response, 19 (39%) had marrow complete response, 19 (39%) had resistant disease, and two (4%) died within 4 weeks of starting treatment. The overall response rate was 57% (95% CI 42-71). The most frequent adverse events during course one of treatment were fever (grade 1-2 in 20 patients, grade 3-4 in nine), hypotension (grade 1-2 in 12 patients, grade 3 in one), and liver-related toxic effects (bilirubin: grade 1-2 in 12 patients, grade 3 in two; raised aminotransferase concentration: grade 1-2 in 27 patients, grade 3 in one). INTERPRETATION Inotuzumab ozogamicin shows promise as a treatment for refractory and relapsed ALL. FUNDING Pfizer.