Intrathecal CNS Prophylaxis Research Articles

A Single Center Experience with Using Dose-Adjusted Repoch in Elderly Patients with Large B-Cell Lymphoma

Background: RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) has been the predominant regimen for treatment of aggressive large B-cell lymphomas (LBCL). In the CALGB 50303 trial, REPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) was associated with similar efficacy but increased toxicity compared to RCHOP, however pts with higher risk disease by International Prognostic Index (IPI) had longer progression-free survival (PFS) with REPOCH therapy in the subgroup analysis ( J Clin Oncol, 2019). Providers may be hesitant to use REPOCH therapy in older, frail patients (pts) with high-risk LBCL due to concern for increased toxicity. One study demonstrated that empirically dose-reduced REPOCH (30-50% dose reduction by age group) was effective and well-tolerated in an elderly population ( Ann Hematol, 2018).A separate study showed significantly reduced neuropathy rates without compromised efficacy when vincristine doses in the REPOCH regimen were capped at 0.5 mg/d compared to 0.4 mg/m 2/d ( Leukemia & Lymphoma, 2019). At our institution, vincristine doses are capped at 0.4 mg/d for all pts, and REPOCH dosing is not empirically dose-reduced based for age alone. The aim of this study is to provide additional insights on the safety and efficacy of REPOCH in elderly pts diagnosed with LBCL with a routine vincristine dose cap of 0.4 mg/day (“REPOCH 0.4”). Methods: In this single cohort study, pts with newly diagnosed LBCL that received dose-adjusted REPOCH 0.4 at a single institution from August 2015 to October 2020 were retrospectively reviewed. Pts were excluded if they received fewer than 2 cycles, had CNS disease, transferred to another facility during treatment, or were lost-to-follow-up. Primary endpoints included adverse effects (AEs), overall response rates (ORR) via Lugano staging at end of treatment, 2y PFS, and overall survival (OS). Survival endpoints were estimated via Kaplan-Meier survival analysis. Secondary endpoints included CNS relapse rates and percentage of pts electing for hospice during therapy. Outcomes were descriptively compared to the historical cohort (N=241) in the CALGB 50303 trial receiving R-REPOCH without a vincristine dose cap ( J Clin Oncol, 2019) . Results: Forty-six pts were eligible for analysis (“entire cohort”), 19 of whom were 70 years or older (“70+ cohort”, figure 1). Median age in the entire and 70+ cohort was 67 and 75 years respectively. In the entire cohort, 23.9% of pts were double-hit, 43.5% had a non-germinal center phenotype, and 78.3% had stage III-IV disease. The median number of REPOCH 0.4 cycles received in both the entire and 70+ cohort was 6. In the 70+ cohort, 57.9% of pts were escalated to a dose level (DL) of 2 or 3 with no pts escalated beyond DL 3. Fifty-eight percent of pts in the entire cohort received intrathecal CNS prophylaxis and all pts received pegfilgrastim support. Pts in the entire cohort were older and higher-risk in comparison to the historical cohort as evidenced by IPI risk and double-expressor status. In the entire cohort, REPOCH 0.4 was well-tolerated (figure 2) with grade 3+ neuropathy rates of only 2.2% (5.2% in the 70+ cohort). Febrile neutropenia (all grades) occurred in 19.5% and 15.8% of the entire cohort and 70+ cohort respectively. Only 1 patient in the 70+ cohort experienced acute ejection fraction (EF) decline during therapy. ORR (complete and partial response) in the entire and 70+ cohort were 80% and 74% respectively. Complete response (CR) rates in the entire and 70+ cohort were both 63%. 2y PFS in the entire cohort was 68.3% (median not reached), and the 2y OS in the entire cohort was 82.9% (median not reached) which compares favorably to the 2y OS of 86.5% in the historical cohort. Overall, only 7% of pts elected for hospice and only 4% experienced CNS relapse. Conclusion: Pts with LBCL 70+ years tolerated dose-adjusted REPOCH 0.4 mg/d similarly to the entire cohort of all ages indicating that empiric dose reduction for age alone isn't necessary. CR rates were similar (63%) with pts 70+ years compared to pts in the entire cohort of all ages. REPOCH 0.4 mg/d was observed to have numerically lower rates of grade 3 or higher neuropathy (2.2%) compared to vincristine 0.4 mg/m 2/d (8.4%, J Clin Oncol 2019) and vincristine 0.5 mg/d dosing strategies (4.5%, Leukemia & Lymphoma 2019) . To our knowledge, this is the first report of outcomes with REPOCH using a vincristine dose cap of 0.4 mg/d.

DA-EPOCH-R for High Grade B-Cell Lymphoma Patients with MYC and BCL2 and/or BCL6 Rearrangements: Clinical Results of the Induction Phase of the HOVON-152 Trial

Introduction Patients (pts) with high grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 gene rearrangements (double hit and triple hit (DH/TH)) have poor outcomes to standard R-CHOP. Retrospective studies reported improved disease-free survival (DFS) through intensification with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). This regimen was studied in a small prospective trial including 24 DH/TH and 19 single MYC rearranged (SH) lymphomas (Dunleavy, Lancet Haematol 2019). No prospective studies evaluating DA-EPOCH-R exclusively for pts with DH/TH HGBL have been reported. The HOVON-152 trial aimed to improve outcomes in untreated DH/TH HGBL pts by investigating the efficacy of the immune checkpoint inhibitor nivolumab as consolidation treatment in pts achieving complete metabolic response (CMR) after DA-EPOCH-R induction. Here, we present the efficacy and safety profile of the induction phase with DA-EPOCH-R. Methods HOVON-152 is a prospective, multi-center, single arm phase II trial. Inclusion criteria were pts with newly diagnosed HGBL-DH/TH (according to the WHO 2016 classification), age ≥ 18 years, WHO performance status (PS) 0-3 and Ann Arbor stage II-IV. During the screening period for rearrangement status, pts could receive 1 cycle of R-CHOP or DA-EPOCH-R, followed by 5 cycles of DA-EPOCH-R. All pts received intrathecal CNS prophylaxis. All diagnostic lymphoma samples were centrally reviewed. PET-CT scans were performed at diagnosis, after 3 cycles and at end-of-induction (local review, central review will be reported at the conference). Pts in CMR after induction treatment (Deauville 1-3 or a negative lymphoma biopsy in case of Deauville 4) proceeded to nivolumab consolidation (480 mg every 4 weeks for one year). The HOVON-152 aimed to improve 12 months DFS of pts in CMR after induction from an expected 70% to 85% with nivolumab consolidation. Secondary objectives included evaluation of response rates, overall survival (OS) and safety. With a power of 0.90 a sample size of 97 pts was calculated. Here, we report efficacy (CMR rate) and safety of DA-EPOCH-R induction treatment. Logistic univariate analysis is used to analyze baseline characteristics associated with response. Adverse events (AEs) were defined according to the common terminology criteria for adverse events (CTC AE 5.0), counted by the highest grade per system organ class per patient. Results From August 2018 - March 2022, 97 pts have been enrolled (study inclusion completed). One patient was excluded due to CNS localization. The median age was 62 years (range 35-79); 90 (83%) pts had stage III-IV disease and 52 (54%) had (intermediate-)high international prognostic index (IPI) (Table 1). Central pathology review confirmed DH/TH in all pts. 65 pts (67%) had a BCL2 DH, 11 (12%) a BCL6 DH and 16 (17%) a TH. Dose adjustments were performed conform protocol. The maximum dose-level (DL) achieved was DL1 in 41 (43%), DL2 in 22 (23%), DL3 in 25 (25%), DL4 in 7 (7%) and DL5 in 1 (1%) of the pts. Vincristine dose was reduced in 28/81 (35%) pts. After DA-EPOCH-R induction, 63/96 (66%, 95% CI 55-75%) pts achieved CMR. WHO PS 2-3 (odds ratio (OR) 0.15, 95% CI 0.03-0.85, p=0.03), elevated LDH (OR 0.24, 95%CI 0.10-0.59, p=0.002) and bulky disease defined as ≥10 cm mass (OR 0.23, 95%CI 0.09-0.56, p=0.001), were significantly associated with a lower chance of achieving CMR. During treatment, 7 (7%) pts experienced a grade 5 AE (ileus, intestinal perforation, multi-organ failure/sepsis). Thereof, 4 patients died during DA-EPOCH-R and 3 patients died after DA-EPOCH-R. 31 (32%) experienced a grade 4 AE (e.g. sepsis, perforation, hemorrhage, thrombocytopenia and neutropenia), 21 (22%) a grade 3 AE (e.g. anemia, mucositis, infections and electrolyte disturbances) and 16 (17%) pts a grade 2 AE. Conclusion We report the largest prospective series of DH/TH HGBL patients treated with DA-EPOCH-R. DA-EPOCH-R induction was feasible, with toxicity and dose adjustments as previously described. The observed CMR rate of 66% was lower than previously reported in a prospective cohort of mixed DH/TH and SH patients (74%). For patients achieving CMR, the nivolumab consolidation phase is ongoing. Translational side studies investigating predictive factors to identify patients not achieving CMR are ongoing. For these patients, novel strategies to improve first-line treatment are warranted.

Linfoma di Burkitt in età pediatrica

Sporadic Burkitt lymphoma (BL) accounts for about 80% of non-Hodgkin lymphomas in childhood and adolescence, with an incidence of 3-5 cases per million in developed countries. The hallmark of LB is the deregulation of MYC oncogene, usually caused by the [t(8;14)(q24;q32)] translocation, involving the gene of immunoglobulin heavy chain. BL is a very aggressive neoplasm, with a doubling time of 12-24 hours and its diagnosis and therapy are a true haematologic emergency. Abdomen, head and neck are the most frequent sites of presentation and the involvement of ileo-caecal area can cause an intussusception as first manifestation of the disease. <br> BL and mature B-cell acute leukaemia (the leukaemic manifestation of BL) share the same therapeutic approach, intensive short courses with multiple alternating chemotherapy agents, the use of high dose-methotrexate and intrathecal CNS prophylaxis. The outcomes are satisfactory: in Italy during the period 1997-2014 the children with BL were treated according to the AIEOP LNH-97 protocol, achieving more than 90% of 5 year-survival. <br> In the last decades, the prognosis for children and adolescents with cancer has dramatically improved and the increasing number of long-term survivors has focused the attention of clinicians on the late effects of cancer and its therapy. A multidisciplinary follow up and a correct transition from the paediatrician to the primary care doctor plays a central role not only in the early detection and therapy of late effects of cancer but also in supporting the patient to realize their physical, mental and social well-being as much as possible.

Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma.

Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late sequelae. We hypothesized that dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R) may obviate the need for highly dose-intensive chemotherapy in adults with Burkitt lymphoma. We conducted a multicenter risk-adapted study of DA-EPOCH-R in untreated adult Burkitt lymphoma. Low-risk patients received three cycles without CNS prophylaxis, and high-risk patients received six cycles with intrathecal CNS prophylaxis or extended intrathecal treatment if leptomeninges were involved. The primary endpoint was event-free survival (EFS), and secondary endpoints were toxicity and predictors of EFS and overall survival (OS). Between 2010 and 2017, 113 patients were enrolled across 22 centers, and 98 (87%) were high risk. The median age was 49 (range, 18-86) years, and 62% were ≥ 40 years. Bone marrow and/or CSF was involved in 29 (26%) of patients, and 28 (25%) were HIV positive. At a median follow-up of 58.7 months, EFS and OS were 84.5% and 87.0%, respectively, and EFS was 100% and 82.1% in low- and high-risk patients. Therapy was equally effective across age groups, HIV status, and International Prognostic Index risk groups. Involvement of the CSF identified the group at greatest risk for early toxicity-related death or treatment failure. Five treatment-related deaths (4%) occurred during therapy. Febrile neutropenia occurred in 16% of cycles, and tumor lysis syndrome was rare. Risk-adapted DA-EPOCH-R therapy is effective in adult Burkitt lymphoma regardless of age or HIV status and was well tolerated. Improved therapeutic strategies for adults with CSF involvement are needed (funded by the National Cancer Institute; ClinicalTrials.gov identifier: NCT01092182).

Characteristics and Outcomes of Lymphoblastic Lymphoma Patients - the University of Miami Experience

BACKGROUND: Lymphoblastic lymphoma (LBL) is an uncommon adult malignancy accounting for <2% of non-Hodgkin´s lymphomas. This high-grade lymphoma is most commonly of T-cell immunophenotype and it is thought to be the nodal/extra nodal presentation of acute lymphoblastic leukemia (ALL). Arbitrarily, 25% bone marrow involvement has been considered cut-off in differentiating between LBL and ALL. The optimal standard treatment for adult with LBL is not yet defined due to rarity of the disease and absence of large randomized prospective studies. Therefore, current recommendation are based on ALL and pediatric population experience. Hyper-CVAD is one of the most commonly utilized regimens for this disease in US. The purpose of this study was to review our experience in LBL patients, most of whom received therapy with Hyper-CVAD regimen followed by POMP maintenance.METHODS: Retrospective review of patients with LBL treated at University of Miami (UM) Health System from January 1995 to June 2015. HIV positive patients were excluded.RESULTS: 32 patients were identified in review of clinical and pathological lymphoma databases. Patients with >25% bone marrow involvement or leukemic presentation in the peripheral blood were excluded. Median age at diagnosis was 34 years (range 17 to 76 years), 23 (72%) patients were male, 14 (44%) were Hispanics, and 30 (94%) had an ECOG performance status of 0-2, and 2 had ECOG of 3-4. 30 (94%) LBL tumors were of T cell origin. Bulky disease was present in 13(41%), mediastinal involvement in 23(72%), pleural/pericardial effusion in 19(59%), SVC syndrome in 6(19%), CNS disease at presentation in 4(12%), and bone marrow involvement (6 to 25%) in 10(31%) patients. 20(62%) patients presented with stage III/IV, 21(66%) with elevated LDH, 13(41%) with B symptoms and 15(47%) patients had high IPI. Median follow-up of all patients was 54 months (range 3.5 to 195months). 30 patients received induction therapy while 2(6%) patients were referred to hospice without receiving any treatment because of their general condition. These 2 patients were excluded from further analyses. 26(87%) of treated patients received Hyper-CVAD (7 received <4 cycles because of side effects and 19 >4 cycles) while others received different ALL-type regimens. 2(6%) patients underwent upfront consolidation with allo-BMT after induction chemotherapy. CR rate was 67% and PR 21%. 13 patients are alive with a median follow up of 63 months (95% CI 75-147). Of the 2 patients treated with allo-BMT one is alive in CR and the other presented CNS relapse after transplant and died of septic shock. Median overall survival (OS) of treated patients was 26 months (95% CI 34-79) and median progression free (PFS) was 21 months (95% CI 29-73). 3-year and 5-year OS rates were both 44% (95% CI 26-61%). 3-year and 5-year PFS rates were 45% (95% CI 26-61%) and 40% (95% CI 22-58%), respectively. Two patients (6%) developed CNS relapse. OS was statistically significantly longer in patients receiving more than 4 cycles of hyper-CVAD (p=0.05). No statistically significantly difference in OS and PFS was associated with following variables: ethnicity, BM involvement, IPI score, stage, presence of bulky disease, ECOG performance status and treatment with mediastinal RT. Patients treated with Hyper-CVAD demonstrated following responses: 17 (65%) achieved CR (95% CI 36-106) and 6(23%) PR (95% CI 0.54-46). Of those who achieved CR 11 are still alive in continuous CR and 6 patients died. Median OS was 26 months (CI: 29-76 months) and median PFS was 21 months (CI: 24-66 months) for Hyper-CVAD treated patients. In these patients 3-year OS and PFS were 44% (95% CI 24-62%) and 44% (95% CI 24-62%), respectively.CONCLUSIONS: Our study describes characteristics and outcomes of patients (mainly indigent) living in Miami area and treated at UM with no referral bias. Many of these patients did not have medical insurance, preventing upfront consolidation with BMT. The observed remission, OS and PFS rates were inferior to rates reported in the literature. However, similar to previous reports, the incidence of CNS relapses was low, suggesting that appropriate intrathecal CNS prophylaxis together with systemic chemotherapy agents penetrating CNS are adequate for CNS prophylaxis. However, our results in this unbiased cohort suggest that either current chemotherapy treatments need be consolidated upfront with BMT or more efficient regimens are needed. DisclosuresNo relevant conflicts of interest to declare.

The role of radiotherapy and intrathecal CNS prophylaxis in extralymphatic craniofacial diffuse large B-cell lymphoma.

8566 Background: The role of radiotherapy and intrathecal prophylaxis in extralymphatic craniofacial involvement of aggressive B-cell lymphoma remains to be determined in the rituximab era. Methods: In a retrospective subgroup analysis of 9 consecutive prospective DSHNHL trials covering all DLBCL risk groups from 18 to 60 years of age, patients with and without craniofacial involvement were compared with respect to clinical presentation, event-free and overall survival. Results: 336 sites of extralymphatic craniofacial involvement were observed in 284/3840 (7.4%) patients (orbita: 30, paranasal sinuses: 90; main nasal cavity: 38, tongue: 26, remaining oral cavity: 99, salivary glands: 53). In a multivariable analysis adjusting for IPI risk factors the addition of rituximab improved EFS and OS in both patients with and without craniofacial involvement. The 141 responding patients who received radiotherapy to sites of craniofacial involvement had a similar 3-year event-free (79% vs 79%; p=0.835) and 3-year overall survival (88% vs. 85%; p=0.311) when compared with the 56 patients who did not receive radiotherapy. Without rituximab, the 2-year-rate of cumulative risk of CNS disease was increased in 205 patients with compared to 2586 patients without craniofacial involvement (4.2% vs. 2.8%; p=0.038), while this difference disappeared in patients who received CHOP(like) chemotherapy in combination with rituximab (1.7% in 77 patients with compared to 2.9% in 946 patients without craniofacial involvement; p=0.868). Of 85 patients with craniofacial involvement who received intrathecal prophylaxis with methotrexate, the 2-year-rate of cumulative risk of CNS disease was 4.3% compared to 2.3% in 189 patients who did not (p=0.995). Conclusions: Rituximab eliminates the increased risk for CNS disease in patients with craniofacial involvement. As a practical consequence intrathecal prophylaxis and radiotherapy to sites of craniofacial involvement should not be given any more.

Rituximab Plus Dose Intense Rapid-Cycling Chemotherapy with Intrathecal CNS Prophylaxis in Patients with Burkitt Lymphoma (BL) and Intermediate Unclassifiable Diffuse Large B-Cell Lymphoma/BL: Single Institution Experience

Abstract 1631Introduction. Burkitt Lymphoma (BL) and the novel category of B-cell lymphoma, unclassifiable, with features intermediate between BL and diffuse large B-cell lymphoma (intermediate DLBCL/BL) listed in the 2008 WHO classification, are mature B-cell non-Hodgkin lymphomas. They were characterized by a high degree of proliferation with an aggressive clinical course. With the introduction of dose intense, rapid-cycling chemotherapy (Magrath 1996), mainly when supplemented with Rituximab, the prognosis of BL was improved. Conversely, the issue of intermediate DLBCL/BL treatment is still a matter of debate. On this basis, we conducted a retrospective analysis to investigate the outcome of adult patients with BL and intermediate DLBCL/BL treated in a single hematological center. Methods. We retrospectively analyzed 23 adult patients divided in two groups according to histological diagnosis treated with Rituximab plus dose intense rapid-cycling chemotherapy with intrathecal CNS prophylaxis. Group 1: 18 adult BL patients, including three with a diagnosis of L3 acute lymphoblastic leukemia, treated according to CODOX-M/IVAC regimen including Cyclophosphamide, Doxorubicin, Vincristine, Methotrexate, Ifosfamide, Etoposide and high dose Cytarabine in association with Rituximab and intrathecal liposomal Cytarabine (R-CODOX-M/IVAC). Group 2: five intermediate DLBCL/BL, treated with Rituximab intensified CHOP with intrathecal Methotrexate followed by high dose Cytarabine and Mitoxantrone and high dose chemotherapy with autologous stem cell transplantation (R-HDC plus ASCT) or with R-CODOX-M/IVAC. Results. Group 1 included 18 patients with a median age of 45 years (range 29–74), stage IV in 14 cases (78%), performance status (PS) 2 in 14 (78%), LDH upper normal value in 13 (72%), bone marrow involvement in eight (44%), B symptoms in eight (44%) and liquor positivity at citoflussimetry in one (5%). Between 2006 and 2011 all 18 patients were treated according to R-CODOX-M/IVAC. Group 2 included five patients with median age of 47 years (range 32–58), stage IV in four patients (80%), PS 2 in all patients, LDH upper normal value in four (80%) bone marrow involvement in three (60%), B symptoms in three (60%) and liquor positivity at citoflussimetry in two (50%). Between 2008 and 2011 two patients were treated with R-HDC plus ASCT while the other three patients were treated with R-CODOX-M/IVAC regimen. All 18 BL patients of group 1 were evaluable for response: 15 patients were in persistent complete remission (CR) and three died of progressive disease. With a median follow-up of 70.3 months, progression free survival and overall survival were 76.5% and 80.3%, respectively. Therapy was well tolerated, with no significant acute and late treatment related toxicities and no toxic deaths. In group 2 the two patients treated with R-HDC plus ASCT died of progressive disease; of the three patients treated with R-CODOX-M/IVAC regimen, one died of early relapse disease occurred three months after achieving CR and two are still on therapy. Conclusions. Our data suggest that in BL R-CODOX-M/IVAC is a safe and highly effective therapeutic regimen providing a high rate of persistent CR. Within the limits of a small sample size, in our experience, patients with intermediate DLBCL/BL have a clinical aggressive disease with a poor prognosis regardless of the type of treatment. Additional and larger studies are warranted to clarify the behavior of this new histological entity and develop novel and efficacy therapeutic approaches. Disclosures:Vitolo:Roche Italy: Speakers Bureau; Celgene: Speakers Bureau; Jannsen-Cilag: Speakers Bureau.

Outcome of APL In Young Children and Adolescents In Two Consecutive Trials of the European APL Group,

AbstractAbstract 507 Background:APL is rare in children (approximately 10% of childhood AML, and 10% of APL) and is characterized by a higher incidence of WBC > 10G/L, microgranular M3 variant (M3v),and bcr2-3 isoforms of PML-RAR rearrangement than in adults. ATRA combined to chemotherapy (CT) is generally considered to give similar overall results in children and adults (De Botton, JCO 2004, Ortega, JCO 2004, Testin, Blood 2005). However, whether children age has an impact on APL outcome is unknown. We compared disease characteristics and outcome of children aged <=12, adolescents (ados), aged 13–18 and adults, aged > 18 included in 2 multicenter trials of the European APL group (APL 93 and 2000) with a median follow up of 10 and 5 years, respectively (resp). Methods:In both trials, pts received induction therapy with ATRA (45 mg/m2/d until CR) and DNR (60mg/m2/d x3d)+/− AraC (200 mg/m2/dx7) followed by consolidation with a similar course and a final DNR (45 mg/m2/d × 3) +/− AraC (1-2 g/m2/12h × 8) course with or without maintenance with intermittent ATRA and/or continuous low dose 6MP+ MTX, during 2 years. ATRA dose during induction was reduced in children to 25 mg/m2/d only in case of side effects. In APL93 trial, pts with WBC<5 G/l were randomized to receive ATRA+CT or ATRA followed by CT during induction, and maintenance was also randomized. In APL2000 trial, pts with WBC<10 G/l were randomized to receive or not Ara C during induction and consolidation courses, while all pts received maintenance and pts with WBC > 10G/L received intrathecal CNS prophylaxis. Results:Of the 833 consecutive newly diagnosed APL pts aged <60y included in the 2 trials, 26 (3%), 58 (7%) and 749 (90%) were aged <=12 (children), 13–18 (ados), and> 18 (adults), resp. Median WBC was 10.8 (range 1.4–148), 2.6 (0,5-77,3) and 2.7 (0,2-183) G/L in children, ados and adults, resp (p=0.0001) and 13/26 (50%), 16/58 (27%) and 187/749 (25%) of them had WBC > 10G/L, respectively (p= 0.038). Median baseline platelets were 23, 23 and 32 G/l in children, ados and adults, resp (p=0.02). M3v subtype was found in 23%, 24% and 13% (p=0.03) across age groups. No imbalance for treatment arms that proved less effective (without maintenance in APL 93, and without AraC in APL 2000 trial) were seen across age groups.CR rates in children, ados and adults were 92%, 100% and 94.5% resp (p=0.1). The frequency of differentiating syndrome did not significantly differ between age groups (16%, 26.7% and 22,8%, resp, Children vs ados p=0.2, overall p=0.6). The 5 year cumulative incidence of relapse (CIR) was 33%, 20% and 23% in children, ados and adults (Children vs ados p=0.3, overall p=0.5), 5-year OS was 75.6%, 93.6%, and 80.4%, resp (Children vs ados p=0.03, overall p=0.03).12 of the 26 children were aged ≤4 years and 14 aged 5–12. Median WBC (8 and 14.8 G/, p= 0.72) and CR rate (91% vs 93%,p=0.72) did not differ in the 2 subgroups. 6 of the 26 children relapsed. 5 of the 6 relapses occurred in pts ≤4 years. Five year CIR was 47% and 18.9% (p=0.03) and 5 year OS was 72% and 78.9% (p=0.62) in children aged ≤4 years and 5–12, respectively. Conclusion:Our results suggest that adolescents with APL have an outcome at least as favorable as that of adults. Children appear to have more relapse, however mainly observed in children <4 years, and correlated with pre-treatment risk factors (especially high WBC counts). Young children may require reinforcement of first line treatment, including possible addition of ATO. Disclosures:Fenaux:CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Isolated central nervous system recurrence of acute promyelocytic leukemia in children

The incidence of isolated central nervous system (iCNS) relapse in pediatric acute promyelocytic leukemia (APL) is debated. We analyzed the literature, focusing on clinical trials reported since the advent of ATRA use. Only 2/218 (0.92%) good risk patients (diagnostic WBC <10,000/microl) had truly iCNS relapse. This incidence does not support the use of intrathecal CNS prophylaxis for all children with APL. We also identified multiple deficiencies in these reports. Additional reporting of these events could provide insight into the true incidence and pathogenesis of iCNS relapse and might allow for identification of risk factors associated with such extramedullary relapse.

Outcome with Hyper-CVAD/MTX-Ara-C, a Dose-Intensive Regimen, in Acute Lymphocytic Leukemia and Highly Aggressive Lymphoma in China.

Purpose: The objective of this study was to evaluate the efficacy and potential toxicity of the Hyper-CVAD/MTX-Ara-C regimen,a dose-intensive regimen, in the patients with acute lymphocytic leukemia (ALL) and highly aggressive non-Hodgkin lymphoma (NHL) in China.PATIENTS AND METHODS: Between June 2004 and June 2007, fifty-six patients with ALL or highly aggressive lymphoma were treated with the Hyper-CVAD/MTX-Ara-C regimen at our institution. Median age was 26 years (range 13 to 60 years), and 35 patients (62.50%) were male. All patients were comprised of 32 previously untreated cases and 24 refractory/relapsed ones. Among the 41 patients with ALL, B-cell disease was present in 82.93%, T-cell disease in 17.07%, and Ph-positive ALL was present in 14.63%, refractory/relapsed disease in 43.90%. Among the 15 patients with highly aggressive NHL, lymphoblastic lymphoma was present in 46.67%, Burkitt's lymphoma was in 53.33% and refractory/relapsed disease in 40.00%. CNS involvement was present in 8% at diagnosis. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and aggressive supportive care with granulocyte colony-stimulating factor (G-CSF), transfusion and antibiotic prophylaxis therapy. Maintenance therapy based on cytogenetics and immunophenotypes in most of patients contained 2-year treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP).RESULTS: The median follow-up time was 7 months (range 1+ to 37+ months). Of the previously untreated 31 patients, twenty-nine patients (93.55%) achieved complete remission (CR) and no patients died during induction therapy. Of the refractory /relapsed 24 patients, fourteen cases (58.33%) achieved CR. Remarkably, the CR rate of the patients with Burkitt's lymphoma was 75.00% (6/8). The median courses finished during the dose-intensive phase were 4 (range 1 to 8), and the median time to delivery of all eight courses was 10 months. The estimated 3-year overall survival (OS) for the untreated and refractory/relapsed patients with ALL was 46.80% and 28.60%, respectively. Meanwhile, the estimated 2-year OS for the aggressive NHL patients was 84.00%. Compared with the patients with ALL who did not receive CR and get less than four courses of this regimen, the patients who did receive CR and get more than four courses of this dose-intensive regimen showed much better OS (p<0.05). The incidence of CNS relapse was low (5%). Myelosuppression-associated complications including documented infections, fever of unknown origin, hemorrhage were the more frequent side effects. Other significant side effects included neurotoxicity, renal and hepatic toxicities, fatigue, mucositis, nausea, vomiting, diarrhea, skin rashes, and G-CSF therapy-associated bone aches.CONCLUSION: The present outcome from our single center in China demonstrated that Hyper-CVAD/MTX-Ara-C, a dose-intensive regimen with much higher CR was superior to our previous regimens, even in patients with highly aggressive lymphoma such as lymphoblastic and Burkitt's lymphoma, and in refractory/relapsed ALL/lymphoma ones. Our study also showed that this regimen was less toxic and well tolerated in most of treated patients in China. Long-term treatment benefits and severe side effects needed further investigation in a well-designed, multiple-center study in China with more eligible patients entering onto the study.

Update of the Modified Hyper-CVAD Regimen with or without Rituximab as Frontline Therapy of Adults with Acute Lymphocytic Leukemia (ALL) or Lymphoblastic Lymphoma (LL).

The hyper-CVAD regimen is an effective therapy program for adult ALL and LL [Kantarjian, JCO18:547, 2000; Kantarjian, Cancer101:2788, 2004, Thomas, Blood104:1624, 2004]. Intensive chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternates with high dose methotrexate and cytarabine every 21 days for 8 courses, followed by maintenance with POMP (6-mercaptopurine, methotrexate, VCR, prednisone). Historical CR rate was 92% with 3-year disease-free survival (DFS) rate of 38%. The regimen was modified in 1999 to address the following: higher induction mortality in patients (pts) aged 60 years or older (17% vs 3%); possible benefit of early anthracycline intensification; worse survival with CD20 expression; and late relapses after completion of POMP therapy. Newly diagnosed or primary refractory (1 course only) ALL or LL pts were treated on two sequential studies. Burkitt leukemia/lymphoma (BLL) and Philadelphia positive ALL pts were treated on separate protocols. From May 2000 to December 2001, 69 pts were treated with the modified regimen as detailed above (9 courses of intensive chemotherapy). Course 2 was eliminated from the second study, with an additional 124 pts were treated (8 courses of intensive chemotherapy). Results were reviewed by lineage (T-cell versus non T-cell), outcome after therapy with rituximab for CD20 positive ALL, and age. Overall CR rate of the group (n=190) was 91%. Median age of the T-lineage pts was 30 (range, 17–74) versus 43 (range, 15–83) for the non-T lineage pts. After a median follow-up of 30 months (range, 6–80), outcome appeared favorable for the younger group aged 30 years or less with 3-year DFS rates of 61% and 66%, and 3-year OS rates of 73% and 71% for non-T and T-lineage, respectively. When comparing outcome of non-T lineage CD20 positive ALL with historical experience, the addition of rituximab appeared to improve DFS rates (56% versus 35%, p=.06) but did not affect survival (62% versus 46%, p=0.23). A subset analysis showed that younger pts aged 30 or less with non T-lineage CD20 positive ALL treated with rituximab had superior outcomes compared with historical experience (DFS rates 62% versus 28%, p=.005; OS rates 73% versus 50%, p=.07). No such benefit of rituximab was observed for the elderly group, in contrast to data previously reported for BLL. Anthracycline intensification appeared to worsen outcome, particularly for T-lineage ALL. Rituximab may benefit subsets of CD20 positive ALL; alternative monoclonal antibodies should be explored. Further improvements in outcome may be achieved with incorporation of novel agents such as nelarabine for T-lineage ALL and sphingosomal VCR for elderly ALL. Modifications to Hyper-CVAD Parameter Hyper-CVAD Modified Hyper-CVAD Laminar air flow rooms No For age [≥ 60yrs or poor PS Dose-intensive anthracycline No C2 Liposomal DNR &amp; cytarabine Rituximab No For CD20 ≥ 20% Intrathecal CNS prophylaxis 4, 8 (16 BL) 6 or 8 (16 BL) POMP 24 months 30 months Intensifications Months 7, 11 Months 6, 7 &amp; 18, 19

Outcome with Hyper-CVAD/MTX-Ara-C, a Dose-Intensive Regimen, in Acute Lymphocytic Leukemia and Highly Aggressive Lymphoma: A Preliminary Study in a Single Center in China.

BACKGROUND: Although the safety and efficacy of the Hyper-CVAD/MTX-Ara-C regimen in hematologic malignancies has been well established by the large clinical trials developed at the University of Texas M. D. Anderson Cancer Center, the outcome with this regimen in patients in China has not been determined. The objective of this study was to evaluate the efficacy and potential toxicity of this regimen in acute lymphocytic leukemia (ALL) and highly aggressive non-Hodgkin lymphoma (NHL) in a single center in China.PATIENTS AND METHODS: Between September 2004 and July 2006,36 patients with ALL or highly aggressive lymphoma were treated with the Hyper-CVAD/MTX-Ara-C regimen at our institution. Median age was 35 years (range 14 to 60 years), and 23 patients (64%) were male. All patients are comprised of 19 previously untreated cases and 17 refractory/relapsed ones. Among the 28 patients with ALL, B-cell disease was present in 82%, T-cell disease in 18%, and Ph-positive ALL was present in 18%, refractory/relapsed disease in 46%. Among the 8 patients with highly aggressive NHL, lymphoblastic lymphoma was present in 63%, Burkitt's lymphoma was in 37% and refractory/relapsed disease in 50%. CNS involvement was present in 8% at diagnosis. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and aggressive supportive care with granulocyte colony-stimulating factor, transfusion and antibiotic prophylaxis therapy. Maintenance therapy according to cytogenetics and immunophenotype in partial patients included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP).RESULTS: The median follow-up was 7 months (range 1+ to 23+ months). Of the previously untreated 19 patients, seventeen patients (89.47%) achieved complete remission (CR) and no patients died during induction therapy. Of the refractory/relapsed 17 patients, seven cases (41.48%) achieved CR. Remarkably, the CR rate of the patients with Ph-positive ALL was 60.00%(3/5), and Burkitt's lymphoma 66.67%(2/3). The median finished courses during the dose-intensive phase were 5 (range 1 to 8), and the median time to delivery of all eight courses was 10 months. The estimated 5-year survival and 5-year CR rates were not concluded so far. The incidence of CNS relapse was low (5%). Myelosuppression-associated complications including documented infections, fever of unknown origin, hemorrhage were the more frequent side effects. Other significant side effects included neurotoxicity, renal and hepatic toxicities, fatigue, mucositis, nausea, vomiting, diarrhea, skin rashes, and G-CSF therapy-associated bone aches.CONCLUSION: The preliminary experience from our single center in China demonstrated that Hyper-CVAD/MTX-Ara-C, a dose-intensive regimen with much higher CR is superior to our previous regimens, even in poor-risk Ph-positive ALL, and highly aggressive lymphomas such as lymphoblastic and Burkitt's lymphoma, and refractory/relapsed ALL/lymphoma. Our data also showed that this regimen is less toxic and well tolerated in patients. Due to the aggressive supportive care, the expense with this regimen is more expensive than conventional chemotherapy. Long-term treatment benefits, such as disease-free survival rates and severe side effects need further investigation in a well-designed, multiple-center study in China with more eligible patients entering onto the study.

Treatment of Newly Diagnosed Acute Promyelocytic Leukemia (APL): A Comparison between French -Belgian-Swiss and Spanish Results.

ATRA combined to anthracycline based chemotherapy is the reference treatment of newly diagnosed APL and a role for maintenance treatment is supported by many studies, but some controversies remain, like the role of AraC.Methods: We performed a joint analysis of pts < 65 yrs included in studies LPA99 (Spanish PETHEMA) and APL 2000 (French -Belgian-Swiss APL group) to address some of those issues. In LPA99, pts received ATRA combined to Idarubicin (IDA) for induction, followed by 3 consolidation courses, 2 with IDA and 1 with mitoxantrone (MTZ, at cumulative dose of 50 mg/m2), and maintenance with intermittent ATRA and continuous 6MP + MTX during 2 years. Pts with high (WBC > 10000/mm3) and intermediate (WBC < 10000/mm3, platelets < 40000/mm3) Sanz score also received ATRA during consolidation courses and higher cumulative dose of IDA (100 mg/m2), vs low risk pts (no consolidation ATRA, cumulative IDA: 80 mg/m2). No AraC was administered in LPA99 trial. For APL 2000, we restricted the analysis to treatment groups that received AraC: pts with low or intermediate Sanz score received induction with ATRA and DNR (60 mg/m2/d x 3) + AraC (200 mg/m2/d x 7) followed by consolidation with a similar course and a final DNR (45 mg/m2/d x 3) + AraC (1 g/m2/12h x 8) course and the same maintenance as in LPA99. High risk patients received the same treatment, but with intrathecal CNS prophylaxis and, in pts < 60 years, AraC 2g/m2/12h x 8 during the last course. Median follow up was 30 and 22 months in LPA99 (412 pts) and APL 2000 (180 pts), respectively. Comparisons were adjusted on age, gender, WBC and platelet counts.Results: In low and intermediate risk patients (308 LPA99 pts, 97 APL 2000 pts), the CR rates, 2 year cumulative incidence of relapse (CIR), EFS and survival were 96% and 99% (p = 0.2), 2.5% and 6.9% (p = 0.05), 93% and 91% (p = 0.6), 95% and 97% (p = 0.3) in LPA99 and APL 2000 trials, respectively. In high risk patients (104 LPA99 pts, 83 APL 2000 pts), the CR rate, 2 year CIR, EFS and survival were 84% and 95% (p = 0.02), 16.0% and 3.3% (p = 0.06), 69.2% and 88.0% (p = 0.01), 82.4% and 91.2% (p = 0.04) in LPA 99 and APL 2000, respectively. Four relapses in high risk pts involved the CNS in LPA99, vs. none in APL 2000. Three and 5 pts in LPA99 and APL 2000 respectively, died in CR, from treatment toxicity.Conclusion: This analysis suggests than in pts with WBC < 10000/mm3, the current PETHEMA approach yields even fewer relapses than a classical ATRA + DNR + AraC regimen, while being less myelosuppressive. This may be due to the anthracyclines used (IDA and MTZ instead of DNR) and/or to the higher cumulative dose of anthracyclines used in LPA99 trial, and possibly also to consolidation ATRA for intermediate risk pts. On the other hand, in pts with high WBC counts, APL 2000 results yielded better EFS and survival and a strong trend for fewer relapses (including relapses involving the CNS), suggesting a beneficial role for AraC, possibly at high dose, in this subset of patients

Clinical Outcome of the Treatment of Adult Acute Lymphoblastic Leukemia (ALL) with the Hyper-CVAD Protocol.

Hyper-CVAD represents an intensified program for the treatment of acute and chronic lymphoid malignancies. This protocol has been proposed as a highly efficient treatment for adult ALL with acceptable toxicity profile.Purpose: In our Institution, Hyper-CVAD was initiated in September 1999 and used as the primary treatment of adult ALL. We analyse and report here our results focusing on the efficacy and the toxicity of the program.Patients and methods: Patient population consisted of 24 de novo ALL (7 T-cell, 17 B-cell). M/F ratio was 11/13, median age 39 yrs,mean age 42,1 yrs (range 18–68 yrs). 7/24(29,1%) patients were older than 50yrs. Hyperleukocytosis of more than 100x109/L was present in 6/24(25%) cases (3 T-cell,3 B-cell), while splenomegaly, hepatomegaly and bulky disease were documented in 19/24, 17/24 and 1/24 cases respectively. Cytogenetic analysis was performed in 23/24 patients: in 11/23 it was normal, in 1/23 showed del(12), in 1/23 revealed just polyploidy and failed in 10/23 cases. Bcr-abl transcripts were detected in three cases. None of our patients presented with CNS disease (morphology & immunophenotyping). Median follow up was 12,5 months (range 1–65 mo). Treatment consisted of four cycles of Hyper-CVAD (including fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone) alternating with four cycles of methotrexate and cytarabine. All patients received intrathecal CNS prophylaxis and granulocyte stimulating factor support. Maintenance therapy consisted of two years of treatment with mercaptopurine, methotrexate, vincristine and prednisone (POMP). Imatinib was added in bcr-abl(+) cases.Results: Hematological complete remission was achieved in 21/24 (87,5%) de novo ALL cases: (11pts <4wk, 10pts >4wk ). Primary resistance was documented in 2/24 cases which subsequently received other therapeutic protocols and eventually deceased. One patient died in early induction. From the group of remmiters 11/21 are alive in CR after median DFS of 21mo (mean DFS 32mo, range 3–57). Another 7/21 remitters-including one post autologous transplantation- relapsed after median of 4,5 mo and six of them deceased. 6/21 patients underwent allogeneic transplantation (4 alive in CR, 2 deceased from complications). Regimen-related toxic deaths occurred in 4/23 cases whilst in remission status. 6/8 Τ-ALLs entered CR but half of them latter relapsed (two in consolidation and one in maintenance). CNS involvement during therapy on hyper-CVAD was not detected in the subgroup of resistant/progressive patients.Conclusions: Within the limitations of the small patient number and relatively short follow up we confirm the effectiveness of hyper-CVAD in de novo ALL, albeight at a lower than expected magnitude. Furthermore, we are unable to confirm the reported excellent outcome in T-ALL. Infectious complications were significant despite the administration of growth factors and prophylactic antibiotics. Hyper-CVAD can prevent leukemia extention to CNS in both responders and non responders.

Favorable outcome with hyper-CVAD in lymphoblastic lymphoma (LL)

6597 Background: Outcome with LL has improved with use of more intensive chemotherapy regimens designed for acute lymphoblastic leukemia (ALL). Methods: From April 1992 to November 2001, 33 patients (pts) with newly diagnosed LL were treated with standard (n=22) [Kantarjian et al, J Clin Oncol 15:547, 2000] or modified (n=11) [Thomas et al, Blood 102:880a, 2003] hyper-CVAD regimens. Courses of hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone were alternated with methotrexate (MTX) and ara-C. The modified regimen inserted liposomal daunorubicin and ara-C for course 2. Mediastinal irradiation (XRT) was planned for bulky mediastinal disease. Intrathecal CNS prophylaxis alternated MTX and ara-C on days 2 and 7 of the first 3–4 courses. POMP (6-MP, vincristine, MTX, prednisone) maintenance was given for at least 2 years, interrupted by intensifications (MTX/asparaginase with or without hyper-CVAD depending on regimen). Results: Median age was 28 yrs (range, 17–59) and 82% were ma...

Favorable outcome with hyper-CVAD in lymphoblastic lymphoma (LL)

6597 Background: Outcome with LL has improved with use of more intensive chemotherapy regimens designed for acute lymphoblastic leukemia (ALL). Methods: From April 1992 to November 2001, 33 patients (pts) with newly diagnosed LL were treated with standard (n=22) [Kantarjian et al, J Clin Oncol 15:547, 2000] or modified (n=11) [Thomas et al, Blood 102:880a, 2003] hyper-CVAD regimens. Courses of hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone were alternated with methotrexate (MTX) and ara-C. The modified regimen inserted liposomal daunorubicin and ara-C for course 2. Mediastinal irradiation (XRT) was planned for bulky mediastinal disease. Intrathecal CNS prophylaxis alternated MTX and ara-C on days 2 and 7 of the first 3–4 courses. POMP (6-MP, vincristine, MTX, prednisone) maintenance was given for at least 2 years, interrupted by intensifications (MTX/asparaginase with or without hyper-CVAD depending on regimen). Results: Median age was 28 yrs (range, 17–59) and 82% were males. 70% had mediastinal disease and 30% had pericardial and/or pleural effusions. Two pts had superior vena cava syndrome and 3 had CNS disease. T-cell immunophenotype was present in 80%. Five (15%) pts had bone marrow involvement. XRT was given to 74% with mediastinal disease. Overall complete remission (CR) rate was 91% (rest with mediastinal disease not qualifying for CR). With median follow-up of 48 months (range, 8 to 110+ months), 23 (70%) pts remained alive without disease. Ten pts progressed within a median of 13 months (6 with standard, 4 with modified hyper-CVAD). Shorter progression-free survival (PFS) was seen in pts with CNS disease at presentation. Three-year PFS was 77% for standard hyper-CVAD and 62% for the modified regimen. Three pts were successfully salvaged with allogeneic SCT. Conclusions: Hyper-CVAD is a highly active regimen which improves outcome in LL compared with conventional ALL regimens. Anthracycline intensification does not appear to improve outcome compared with standard hyper-CVAD. Incorporation of newer agents such as Campath and nelarabine could be considered for slow responders or those with residual mediastinal disease. No significant financial relationships to disclose.