ALBERT

Description: Introduction: Hyperbilirubinemia is a well known side-effect of L-asparaginase. Grade 4 hyperbilirubinemia (bilirubin 〉 3) results in delayed chemotherapy; compromising dose intensity. Hence a strategy to prevent this is important. Materials & Methods: At our center, we see around 125 cases of newly diagnosed adult acute lymphoblastic leukemia (age〉24 years) every year. Since 2005, we have started treating these adult patients on modified BFM 90 protocol. This protocol includes 8 doses of L-asparaginase at 10,000 units/m2 during induction. Hyperbilirubinemia of grade 4 (median bilirubin upto 20) was encountered in the first few patients. To avoid delay in chemotherapy, we modified the protocol to cap L-asparaginase dose at 10,000 u for all patients. Results: A total of 64 patients with ALL was treated on this modified protocol in 18 months. We compared the degree of hyperbilirubinemia in this group of patients with the first 20 patients who were treated with the standard dose of L-asparaginase. Median age of the full cohort (All 84 patients) was 34 years (24–60). Fifty four patients had precursor B-cell ALL while 30 patients had T-cell ALL. Male: Female ratio was 4.1:1. All the analysed patients have completed induction. In first group of 20 patients who had received standard dose of L-asparaginase, 6 patients developed grade 4 hyperbilirubinemia (median bilirubin 23). SGPT, SGOT and SAP were either normal or borderline elevated. Viral markers at diagnosis and at the onset of hyperbilirubinemia were negative. No significant hepatic abnormality was seen on USG abdomen. In four out of 6 patients’ bilirubin returned to normal after conservative management, over a period of 3 weeks. The two remaining patients developed sepsis, had deranged coagulation parameters and succumbed to sepsis. Of the second group of 64 patients ( L-asparaginase at 10,000 fixed dose), 5 patients developed hyperbilirubinemia (highest value of bilirubin 4). All other investigations (listed above) were normal.All patients’ bilirubin came back to normal within 1 week of interruption of chemotherapy. Complete remission rates were 90% in the first group of 20 patients and 92% in the second group of 64 patients. Conclusion: In the cohort of 64 patients (second group), capping of L-asparaginase resulted in significant reduction in intensity, incidence and duration of hyperbilirubinemia. This modification did not affect CR rate, though we are currently evaluating long term survival to confirm sustained efficacy.

Description: Background: Elderly cancer patients are underrepresented in cancer services utilization and clinical research in India. National data on providers’ knowledge, attitude and practices with regard to elderly cancer patients is sparse and is urgently required to address needs of this vulnerable and growing population. Methods: A self administered questionnaire was mailed to nationally representative sample of practicing oncologists all over India. 74 Oncologists (Medical Oncologists-58%; Radiation Oncologists-25%; Surgical Oncologists-12%; allied fields-6%) responded out of 〉 250 mailed Questionnaires (response rate-29%). Results: Majority (52%) of respondents considered patients with chronological age of 〉60 years as elderly. Although 75%(median) of elderly patients receive some therapy, only 50% of early stage-potentially curable patients and a similar percentage of advanced stage-potentially incurable patients receive curative and palliative therapies respectively. Also, half of treated patients require modification in their treatment approach and only two-third of treated patients complete therapy. The existent barriers to treatment included poor performance status (51%), advanced stage (18%), co-morbidities (14%) and financial constraints (8%). Only 50% Oncologists always discussed and 31% always enrolled elderly patients in clinical trials. Inadequacies with respect to care and evidence based recommendations for elderly patients as compared to young patients were felt by 47% and 92% of respondents respectively. The need of separate trials for elderly and a separate discipline of Geriatric Oncology was voiced by 92% and 87% of participants respectively. Major differences in treatment practice between Hemato-oncologists and non Hemato-oncologists are highlighted in table-1. Conclusions: Treatment practices and clinical trial accrual of elderly cancer patients in India is far from optimal. Formation of a National Geriatric Oncology society with a focus on research and treatment in this vulnerable group may enhance the understanding and clinical care of this growing population. Table-1 : Differences in the treatment practice between Hemato-oncologists and non Hemato-oncologists Treatment Practice Hemato-oncologists(%) Non Hemato-oncologists(%) *Patients given therapy as a percentage of those eligible Age cut-off for elderly ≥60 years 59 39 Palliative therapy * 60 30 Curative therapy * 50 75 Discuss trials with patients 42 64 Enroll patients in trials 36 21 Felt inadequacy in care 52 39 Felt inadequacy in evidence based recommendations 96 85 Felt need for seperate trials 96 85

Description: OBJECTIVE: ALCL is a rare but biologically well characterized disorder. Though ALCLs are highly chemo-sensitive, 20% to 40% of patients develop recurrent disease. No standard therapeutic regimen exists for the treatment of ALCL. The objective of the present study is to characterize the clinical features and treatment response of children and young adults with ALCL in India Methods: 30 patients of ALCL who were previously untreated were enrolled between Jan 1991 and July 2006. Treatment consisted of eight alternating cycles of two regimens A and B. Regimen A included Cyclophosphamide, Adriamycin, Vincristine and Cytosine-arabinoside. Regimen B included Etoposide, Vincristine, Methotrexate (standard dose), and Ifosfamide with Mesna. Intrathecal Methotrexate and Cytosine Arabinoside were administered in the first 4 cycles (MCP 842. Ann. Oncol.1997; 8: 893). No high dose chemotherapy or radiotherapy was given. Since Jan. 2004, Vincristine was replaced with Vinblastine and patients received 6 months (Stg. I and II) or 12 months (Stg. III and IV), of oral maintenance therapy with 6-MP and Methotrexate (11 patients). Results: The median age was 14 years (range 2.6 to 31 years). The male to female ratio was 2.8:1. Common predominant disease sites included: Abdomen-27%; Nodes-33%; Bones-17%, Head and Neck-10%; and Mediastinum-13%. Four patients (13%) presented with stage I disease, 7 (23%) with stage II, 14 (47%) with stage III and 5 (17%) with stage IV. The response rate was 93% for the 29 evaluable patients (1 still on second cycle), with complete response in 86%. There were 6 relapses (20.7%) with majority (83%) of relapses showing newer sites of involvement. For the whole group, the projected 10 year EFS was 52.7% and OS was 73.3%. The EFS analyzed stage wise was 66.7% and 44.1% for localized Stages (I and II) and advanced Stages (III and IV) respectively. For the 20 post-2000 patients, the probability of 5 yr. OS is 100% (Stg I and II) and 84.4% (Stg III and IV) (3 relapsed patients have received Vinblastine based chemotherapy and are in subsequent remission). Most importantly, the EFS so far is 100% for all 11 patients treated with Vinblastine and maintenance therapy. Conclusions: Most Indian patients with ALCL present in advanced stages with abdomen and nodes as the dominant primary sites of disease. Although, in the past, initial treatment responses were good, long term survival was suboptimal due to relapses. Simple addition of Vinblastine and oral maintenance may improve EFS in ALCL without the need of adding high dose or more aggressive CT. This protocol would be especially useful to treat both children and adults with ALCL in countries with limited resources & supportive care.

Description: Background: Despite successful treatment with ATRA and chemotherapy (CT), nearly 10% of APL patients die during early part of treatment because of life threatening complications like bleeding, thrombosis, Retinoic Acid Syndrome (RAS) or infection. This number increases to 〉20% in most developing countries and presents significant challenge for clinicians. The goal is to develop therapy that rapidly corrects coagulopathy and also normalizes counts. Recent in-vitro data had suggested that G-CSF markedly and selectively stimulates the differentiating effect of ATRA in APL cells without increasing apoptosis. The objective of this pilot study was to evaluate the effect of G-CSF given along with ATRA during induction therapy in patients with APL. Patients and Methods: From 2003, 25 patients (ages 1 yr to 43 yrs; median 24 yrs) with APL ineligible for standard CT were treated on a pilot study with Oral CT: Prednisolone 40 mg/m2/d, Etoposide 50 mg/m2/d & 6TG 40 mg/m2/d (PET) for 21 days as induction therapy along with ATRA (45 mg/m2/d for 90 days) (Blood2005;106:900). On completion of oral CT, G-CSF (5 mg/kg/d) was added after day 25 to ATRA in 12 patients in view of persistent cytopenia (low ANC &/or platelets). Results: Patients received a median of 4 doses of G-CSF (range 2–12). The median ANC before starting G-CSF was 0.493 × 109/L (range 0.014–4.21) which increased to a median of 1.78 × 109/L (range 0.525–13.0) post G-CSF (〉 1.0 × 109/L in 10/12 patients). Interestingly, platelet count which was 〈 50.0 × 109/L in 8/12 patients (median 44.15 × 109; range 12–178) prior to G-CSF, increased to 〉 100.0 × 109/L in all except one patient (median 177 × 109; range 64–357). Comparison of pre and post G-CSF cytogenetic status by FISH showed significant decrease in t (15; 17) positivity post ATRA-G-CSF exposure (78-0; 80-11; 54-10). In rest nine patients the bone marrow cytogenetic studies were done post G-CSF only. Complete morphological, cytogenetic and molecular remission was achieved in 9 patients (75%) at a median of 40 days. None of the patients developed RAS, bleeding or thrombotic complications. Presently all 12 patients continue to be in molecular remission at a median follow-up of 17 months (range 9–35 months). Conclusions: There is still a valuable role of single institutional trials in exploring innovative therapies in APL. Chemotherapy, ATRA and arsenic trioxide, all induce apoptosis which causes over expression of Annexin II, which in turn increases plasmin generation and thrombin generation. However, when G-CSF is used in combination with ATRA, neither proliferation arrest nor induction of apoptosis precedes the differentiation. Thus, use of G-CSF along with ATRA very early in therapy of APL may help to decrease or avoid the early life-threatening coagulation abnormalities. Also, rapid improvement in ANC and platelet count could decrease the other induction complications of infection & bleeding, further improving survival.

Description: Introduction Subcutaneous (SC) omacetaxine mepesuccinate (OMA) is indicated for the treatment of CP and AP CML in adults with resistance/intolerance (R/I) to ≥2 tyrosine kinase inhibitors (TKIs). Unlike TKIs, OMA inhibits protein synthesis and is not a direct inhibitor of Bcr-Abl kinase activity. The clinical activity of OMA was demonstrated in a combined cohort of patients from 2 single-arm trials. The cohort consisted of patients who had received ≥2 approved TKIs and, at a minimum, documented evidence of R/I to dasatinib and/or nilotinib. This is the final ≥24-month follow-up analysis in a cohort subset from the 2 studies as originally approved by the FDA. Methods Patients received OMA 1.25 mg/m2 bid SC in 28-day cycles: 14 days for induction and 7 days as maintenance, adjusted for tolerability. Primary endpoints were major cytogenetic response (MCyR) for CP and major hematologic response (MaHR) for AP. Secondary objectives included time to onset and duration of response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Survival data were collected after study discontinuation. Efficacy was analyzed by a data monitoring committee (DMC) on-study and investigators during follow-up for the cohort used for approval of OMA, which excluded patients with a best response at baseline or from a site without verified protocol compliance. Safety was analyzed for all CP and AP patients receiving SC OMA. Results As of October 12, 2012, the efficacy analysis cohort included 76 CP and 35 AP patients. The safety group included 163 patients (108 CP and 51 AP, plus 4 AP patients from a prior study). The majority of the 76 CP (median age, 59 y; range, 26-83 y) and 35 AP patients (median age, 64 y; range, 23-83 y) had received hydroxyurea (CP 41/76, AP 22/35) and 3 prior TKIs (CP 36/76, AP 22/35). At data cutoff, 5 CP patients and 1 AP patient continued OMA treatment (CP: 57, 43, 57, 52, and 48 months; AP: 52 months). Median treatment duration was 7.5 (range, 0-55.6) months for CP and 1.6 (0-49.7) months for AP patients. Median total months of follow-up for survival was 29.5 (95% CI, 17.6-36.4) for CP and 14.3 (95% CI, 4.7-18.7) for AP patients. Of patients receiving ≥2 cycles, 53/60 CP and 16/26 AP patients had a cycle delay; median number of cycles requiring delay per patient were 4 (CP) and 1 (AP). DMC-assessed responses were unchanged at 24 months; only investigator assessments were performed during follow-up. The MCyR rate for CP was 18% (14/76) with a mean time to onset of 3.5 months and median duration of 12.5 months. For AP, the MaHR rate was 14% (5/35) with a mean time to onset of 2.3 months and median duration of 4.7 months. No AP patients achieved MCyR. For ongoing patients, responses at data cutoff were complete cytogenetic response for all CP patients and hematologic improvement for the AP patient. Median PFS was 9.6 months for CP and 3.6 months for AP patients. At data cutoff, 16 CP and 1 AP patients had not progressed. Survival data were collected after therapy discontinuation; however, of the 6 patients in the efficacy cohort who remained on treatment at data cutoff, 2 (both CP) lost response as assessed by investigators. Based on the 24-month update, median OS was extended from 33.9 to 40.3 (95% CI, 23.8 to not reached) months for CP patients and was unchanged for AP patients at 14.3 (95% CI, 6.7-18.7) months (Figure). Safety and tolerability across the 24-month analysis were unchanged from the original analysis. The most common AEs (≥20%) were thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, and pyrexia for CP and AP patients; leukopenia and headache were ≥20% for CP only; febrile neutropenia was ≥20% for AP only. Patients with severe myelosuppression were at risk for infections and hemorrhage. Grade 3/4 hematologic laboratory toxicities for CP and AP patients were thrombocytopenia (CP 92/108, AP 44/50), neutropenia (CP 88/108, AP 35/50), leukopenia (CP 82/108, AP 30/50), and anemia (CP 65/108, AP 39/50). There were 53 deaths in the CP and 38 in the AP groups in the ≥24-month period; the most common causes were disease progression (25, 15), unknown (13, 17), sepsis (5, 0), and hemorrhage (cerebral [2, 3], pulmonary [1, 1]). Conclusions This 24-month update demonstrates that OMA induces clinically meaningful and durable responses in a subset of heavily pretreated patients with CP or AP CML who failed prior TKI therapies. Most grade 3/4 AEs were related to myelosuppression. Support: Teva BPP R&D, Inc. Disclosures: Cortes: BMS : Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Wetzler:Teva: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Lipton:Ariad: Consultancy, Equity Ownership, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding. Khoury:Teva: Honoraria. Michallet:Astellas: Honoraria; Merck: Honoraria; Genzyme: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Research Funding; Teva: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Baccarani:BMS: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Teva: Consultancy; Novartis: Consultancy, Honoraria. Rea:BMS: Honoraria; Teva: Honoraria; Novartis: Honoraria. Chuah:BMS: Honoraria; Novartis: Honoraria. Parikh:Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Dr Reddys: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Glenmark: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Spectrum Pharmaceuticals: Equity Ownership; OncoRx: Equity Ownership; Biocon: Research Funding; GSK: Research Funding; Intas: Research Funding; Alkem: Research Funding. Li:PharmaStat, LLC: Consultancy. Munteanu:Teva: Employment, Equity Ownership. Brown:Teva: Employment, Equity Ownership. Nicolini:Novartis: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Teva: Honoraria; Ariad Pharmaceuticals: Honoraria; Pfizer: Honoraria.