Background: AML M0 has dismal complete remission (CR) rates (<50% in most series) and poor long term survival with conventional combination chemotherapy (CT). Thus it is considered a candidate for allogenic bone marrow transplantation (BMT) in first remission and also for other novel therapeutic approaches. There is increasing recognition of angiogenesis as a pathogenic and prognostic factor in AML. The objective of our study was to evaluate the efficacy of low-dose oral metronomic CT in patients with AML-M0. Materials and methods: Eleven patients fulfilling the diagnostic criteria for AML-M0 and ineligible for standard CT and/or BMT were accrued in this pilot protocol between June 1998 and Feb 2005. The treatment consisted of Prednisolone 40 mg/m2/d, Etoposide 50 mg/m2/d and 6-TG 40 mg/m2/d (PET), given orally on out-patient basis continuously for 21 days every month. Post-induction high dose Ara-C (HD-Ara-C) was given whenever possible. Results: The median age was 17 yrs (range 1.5 to 52); 9 were males and 2 females. The median leukocyte count at presentation was 15.4 x 109/L (range 0.9 to 142) and platelet count was 62 x 109/L (range 21 to 442). CD56 and CD7 were positive in 3/5 and 8/11 of those evaluated. Cytogenetic studies were done in 7 patients. Ten of the eleven patients received at least 1 cycle of PET CT of which 9 (90%) achieved CR. The eleventh patient received only 1 week of CT before being lost to follow up, however by then she had already cleared all blasts (57%) in the peripheral blood. Importantly the whole induction was given on out patient basis with only 2 patients requiring admission. There was minimal to nil blood, platelet and antibiotic support required during the entire Induction therapy. Four of them received HD-Ara-C after achieving CR; two of them died in remission at 6 and 11 months. The other two are alive in CR at 36 months and 14 months. Others who could not get HD-Ara-C because of socio-economic reasons were continued on PET or ET chemotherapy for up to maximum of 12 cycles. The median overall survival was 20 months for those who continued treatment. So far no relapses are noted in those who received PET x 2 followed by HD-Ara-C. Conclusions: The dramatic remission rates, excellent tolerability, minimal cost and morbidity with this protocol provide proof of principle that metronomic approach may be a superior alternative to conventional induction chemotherapy in the treatment of AML-M0. Additionally, incorporation of HD-Ara-C consolidation and metronomic maintenance may improve the long term outcome of this disease with dismal prognosis.
Background: The prognosis of APL has improved markedly with the use of All-Trans-Retinoic Acid (ATRA), but many patients in developing countries are in the high-risk group at presentation and because of inadequate infrastructure die during aggressive induction therapy due to either sepsis or bleeding and/or ATRA syndrome. There is growing appreciation of pivotal role of angiogenesis in APL (Blood2001; 97: 3919). The objective of our study was to evaluate the efficacy of low-dose oral metronomic CT during induction and maintenance therapy along with ATRA in APL. Materials and Methods: From 2003, 23 patients (ages 1 yr to 43 yrs; median 24 yrs; 13 females, 10 males; median WBC count 5.09 X 109/L, range 0.5 to 113 X 109 /L; 7 low risk, 7 intermediate risk & 9 high risk) with APL who could not go for standard CT were included. ATRA 45 mg/m2/d was given for 90 days. Oral CT was given with Prednisolone 40 mg/m2/d, Etoposide 50 mg/m2/d and 6-TG 40 mg/m2/d (PET) for 21 days as induction therapy with ATRA. Consolidation was with 3 cycles of single agent Daunorubicin at 45 mg/m2/d on d 1, 2, 3 every 21 days. This was followed by 6 cycles of oral ET/PET. ATRA was continued for 15 days every 3 months for total of 18 months. Results: The protocol was well tolerated on out-patient basis and after the initial admission at presentation, only 6 patients required readmission. Complete morphological, cytogenetic and molecular remission was achieved in 21 patients (91.3%) at a median of 40 days. There were 2 septic deaths during induction; only 1 patient developed ATRA-syndrome once started on PET. There was 1 remission death because of disseminated chickenpox and 1 patient had CNS relapse. Projected Event Free Survival (EFS) and Overall Survival (OAS) at 24 months is 73% and 84% respectively which is significantly better than our previous results (Am J Hematol1999; 60:87). Interestingly the CR rate and OAS for the 9 high risk patients is 100% so far. Conclusions: There is a valuable role of single hospital trials in exploring innovative therapies in APL. This pilot study contributes to discussion of 4 more debated issues (1) Is there a role for Ara-C in the treatment of APL. (2) How can one improve the therapy in high risk patients without increasing toxicity, (3) What is the ideal duration of maintenance therapy, and (4) What is the ideal therapy for elderly patients and for those who are known to have appreciable mortality from aggressive chemotherapy.
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.
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.
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