Complete Remission Duration Rates Research Articles

The Impact of Smoking on Survival in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Treated with the Combination of Intensive Therapy with Tyrosine Kinase Inhibitor (TKI)

The Impact of Smoking on Survival in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Treated with the Combination of Intensive Therapy with Tyrosine Kinase Inhibitor (TKI)

Updated results of frontline ofatumumab-hyper-CVAD in adults with CD20+ acute lymphoblastic leukemia.

7033 Background: Chemoimmunotherapy is an effective frontline therapy for acute lymphoblastic leukemia (ALL). Ofatumumab (O) binds to a proximal small-loop epitope on CD20 and is more potent in vitro than rituximab. Here we report interim results of its combination with hyper-CVAD (HCVAD) in adult patients (pts) with CD20+ ALL. Methods: Since 7/2011, we have enrolled 63 pts with Ph-negative CD20+ ALL (59 newly diagnosed, 4 previously treated). For the intensive phase, pts received 4 cycles (cy) of HCVAD (odd cy 1, 3, 5, 7) alternating with 4 cy of methotrexate-cytarabine (MTX-Ara-C, even cy 2, 4, 6, 8), and ofatumumab during cy 1-4. For maintenance, pts received POMP for ~30 months (mos), and intensification with MTX/PEGylated asparaginase on mos 6 and 18, and O-HCVAD on mos 7 and 19. Intrathecal MTX-Ara-C was used for CNS prophylaxis. Bulky mediastinal disease was irradiated when indicated. Results: Median age was 41 years (range: 18-71) and median WBC count was 4.6 x109/L (range: 0.6-201 x109/L). 22 pts (35%) had diploid cytogenetics and 8/35 pts (23%) had TP53 mutation. CD20 expression was > 20% in 38 pts (60%), 10-20% in 6 pts (10%) and 1-10% in 16 pts (25%). Median follow-up was 20 mos (range: 1-58) and median number of cy was 8 (range: 1-8). 3 pts (5%) were in CR at the time of enrollment. Of 60 pts evaluable for response, 58 pts (97%) achieved CR; 1 pt achieved CRp and 1 pt died during cy 1 from sepsis. Flow cytometric minimal residual disease (MRD) was negative in 57/62 pts (92%) overall, and in 36/57 pts (57%) at CR. Median time to negative MRD was 0.7 mos. Median time to platelet and neutrophil recovery in cy 1 was 21 and 18 days, respectively. The most common grade 3/4 non-hematological toxicities were infections during induction (49%) and consolidation (72%), elevated transaminases (35%), and hyperbilirubinemia (21%). 5 pts (7%) experienced a grade 3/4 transfusion reaction. 8 pts (13%) received stem cell transplantation in CR1. 10 pts (16%) have relapsed (8 morphological, 2 MRD only). Overall survival and 2-year CR duration rates were 80% and 81%, respectively. Survival outcomes were independent of percentage of CD20 expression. Conclusions: O-HCVAD is safe, effective and results in durable responses in pts with CD20+ ALL. Clinical trial information: NCT01363128.

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

Various trials have reported improved outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) who received treatment with pediatric-based regimens. Those reports prompted the current investigation of the pediatric augmented Berlin-Frankfurt-Münster (ABFM) regimen in AYA patients. The results were compared with those from a similar population that received the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen. Eighty-five patients ages 12 to 40 years who had Philadelphia chromosome (Ph)-negative ALL received the ABFM regimen from October 2006 through April 2012. Their outcome was compared with outcomes in 71 historic AYA patients who received hyper-CVAD from the authors' institution. Patient and disease characteristics, as well as minimal residual disease status, were analyzed for their impact on outcomes. The complete response rate with ABFM was 94%. The 3-year complete remission duration (CRD) and overall survival (OS) rates were 70% and 74%, respectively. For patients aged ≤21 years, the 3-year CRD and OS rates were 72% and 85%, respectively; and, for patients ages 21 to 40 years, the respective rates were 69% and 60%. The initial white blood cell count was an independent predictive factor of OS and CRD. The minimal residual disease status on days 29 and 84 of therapy also were predictive of long-term outcomes. Severe regimen toxicities included transient hepatotoxicity in 35% to 39% of patients, pancreatitis in 11% of patients, osteonecrosis in 11% of patients, and thrombosis in 22% of patients. The 3-year OS rate was 74% in the ABFM group versus 71% in the hyper-CVAD group, and the corresponding 3-year CRD rate was 70% versus 66%, respectively. ABFM was tolerable in AYA patients with ALL but was not associated with significant improvements in CRD and OS compared with hyper-CVAD.

Outcomes Continue to Be Favorable for De Novo Philadelphia Chromosome Negative B-Lymphoblastic Leukemia (ALL) After Therapy with Hyper-CVAD (with or without Rituximab) Regimen

AbstractAbstract ▪3572▪This icon denotes a clinically relevant abstractThe hyper-CVAD regimen [Kantarjian, JCO 18: 547, 2000; Kantarjian, Cancer 101: 2788, 2004] includes intensive cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternating with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone) interrupted by early and late intensifications. The regimen was modified in 1999 to include use of laminar air flow rooms during the induction phase for patients (pts) aged 60 years or older. Therapeutic modifications included rituximab 375 mg/m2 (Days 1 & 11 of hyper-CVAD, Days 1 & 8 of MTX-cytarabine for 8 total doses) for CD20 expression > 20% to counteract increased propensity for relapse [Thomas D, Blood 113: 6330, 2009], early anthracycline intensification with liposomal daunorubicin-cytarabine from 1999–2000 only [omitted thereafter owing to lack of benefit, Thomas D, Cancer 116: 4580, 2010], augmentation of CNS prophylaxis, and extension of maintenance POMP therapy from 24 to 30 months with additional early and late intensifications [details in Thomas D, JCO 28: 3830, 2010]. Overall, 216 pts with Ph negative B-lymphoblastic leukemia have been treated with the modified hyper-CVAD regimens. Median age was 46 years (range, 16–84). For the CD20 positive B-lymphoblastic subset treated with hyper-CVAD and rituximab 3-yr rates of CR duration (CRD) and survival (OS) were 66% and 57%. In the younger (age < 60 years) CD20-positive subset, rates of CRD and OS were superior compared with standard hyper-CVAD (69% v 38%; P <.001% and 71% v 47%, P =.003). Historical experience in 37 adolescent and young adult (AYA) subset aged 15 – 30 yrs with CD20 positive B-lymphoblastic leukemia (prior to shift to augmented BFM regimen as first line therapy) showed that the addition of rituximab improved 3-yr CRD rates from 26% to 60% (P =.001) and 3-yr OS rates from 47% to 70% (P =.05) compared with standard hyper-CVAD without rituximab. There were no significant differences in outcome for this AYA subset by regimen (standard or modified) for the CD20 negative groups (all 3-yr rates > 70%). Elderly pts aged 60 year or older with CD20 positive B-lymphoblastic leukemia treated with hyper-CVAD and rituximab, in contrast to the Burkitt experience, had outcomes which were similar to the historical experience with standard hyper-CVAD (rates of CRD 59% v 50%, P = NS and OS 23% v 32%, P = NS, respectively), despite high rates of negativity for minimal residual disease (MRD) by multiparameter flow cytometry (MFC) at CR, related mainly to deaths in CR during consolidation. MRD positivity by MFC after induction therapy with hyper-CVAD and rituximab was associated with a higher relapse rate and lower 3-yr CR duration rates compared with MRD negative status at the time of CR. Additional doses of rituximab were added to consolidation (Day 1 of cycles 5 – 8) and maintenance chemotherapy in order to potentially improve outcomes for the MRD positive subset. Upfront dose reductions of cyclophosphamide, doxorubicin, vincristine, dexamethasone and methotrexate have been implemented for all cycles of induction-consolidation phase for older age and/or poor performance status with reduction in rate of deaths in CR noted. Incorporation of pegylated asparginase (one dose of 2000 Units/m2 with capping per cycle, 1000 Units/m2 if older or poor performance status) during the induction-consolidation phase (“augmented hyper-CVAD”) was piloted as first line therapy in 19 pts aged 30 – 59 years of age, then omitted owing to excessive toxicity. Incorporation of rituximab into first line intensive chemotherapy such as the hyper-CVAD regimen appears beneficial for younger pts, prompting investigation of second generation anti-CD20 monoclonal antibodies such as ofatumumab and hyper-CVAD (regardless of CD20 expression owing to data showing upregulation of CD20 expression) for the younger subsets and inotuzumab (with or without rituximab) and “mini-hyper-CVAD” for the elderly group. Multivariate analysis of outcomes by risk groups (age/MRD status/CD20 expression) and the impact of the early/late intensifications during maintenance chemotherapy will be presented. Disclosures:O'Brien:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Twice-Daily Fludarabine and Cytarabine Combination With or Without Gentuzumab Ozogamicin is Effective in Patients With Relapsed/Refractory Acute Myeloid Leukemia, High-Risk Myelodysplastic Syndrome, and Blast- Phase Chronic Myeloid Leukemia

We evaluated the efficacy and safety of the combination of twice-daily fludarabine and cytarabine (BIDFA) in patients with refractory/relapsed acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), and chronic myeloid leukemia in myeloid blast phase (CML-BP). One hundred seven patients were enrolled. Overall, 27 (26%) patients responded with a complete remission (CR) rate of 21% and CR without platelet recovery (CRp) of 5%. The overall 4-week mortality rate was 9%. In conclusion, BIDFA is active and safe in heavily pretreated patients with myeloid malignancies. The purpose of this study was to evaluate the efficacy and safety of the combination of twice-daily fludarabine and cytarabine (BIDFA) in patients with refractory/relapsed acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), and chronic myeloid leukemia in myeloid blast phase (CML-BP). One hundred seven patients with refractory/relapsed AML, intermediate and high-risk MDS, and CML-BP, with a performance status of 3 or less and normal organ function were treated. Patients received fludarabine 15 mg/m(2) intravenously (IV) every 12 hours on days 1 to 5 and cytarabine 0.5 g/m(2) IV over 2 hours every 12 hours on days 1 to 5. Gemtuzumab ozogamicin (GO) was administered at 3 mg/m(2) IV on day 1 in the first 59 patients. Patients with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors. Overall, 27 (26%) patients responded with a complete remission (CR) rate of 21% and CR without platelet recovery of 5%. The overall 4-week mortality rate was 9%. The CR rates for patients with relapsed AML with first CR duration greater than or equal to 12 months, relapsed AML with first CR duration less than 12 months, and refractory/relapsed AML beyond first salvage were 56%, 26%, and 11%, respectively. With a median follow-up of 7 months, the 6-month event-free survival, overall survival, and complete remission CR duration rates were 18%, 35%, and 70%, respectively. BIDFA is active with an overall response rate of 26% in a heavily pretreated population. This combination is safe with a low 4-week mortality rate of 9%.

Outcomes for Adult Lymphoblastic Leukemia (ALL) Are Mainly Influenced by Age and Status of Minimal Residual Disease (MRD) by Multiparameter Flow Cytometry (MFC) After Therapy with the Modified Hyper-CVAD (with or without Rituximab) Regimen

Abstract 1524The hyper-CVAD regimen is an effective frontline program for de novo adult ALL [Kantarjian, JCO 18: 547, 2000; Kantarjian, Cancer 101: 2788, 2004]. Intensive cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternate with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone) interrupted by early and late intensifications. The regimen was modified in 1999 to include use of laminar air flow rooms during the induction phase for pts aged 60 years or older. Rituximab 375 mg/m2 (Days 1 & 11 of hyper-CVAD, Days 1 & 8 of MTX-cytarabine for 8 total doses) was administered for CD20 expression > 20% to counteract increased propensity for relapse [Thomas D, Blood 113: 6330, 2009]. Early anthracycline intensification with liposomal daunorubicin and cytarabine was incorporated from 1999–2000 then omitted from the regimen [Thomas D, Cancer 116: 4580, 2010]. CNS prophylaxis alternated intrathecal MTX day 2 with cytarabine day 7 of the first 3 courses for low CNS risk and first 4 courses for high CNS risk (in the absence of CNS disease). Maintenance therapy was extended from 24 to 30 months inclusive of early and late intensifications (hyper-CVAD followed by weekly MTX and L-asparaginase mos 6 & 7 then mos 18 & 19) to reduce incidence of late relapses. Results in the CD20 positive B-lymphoblastic subset treated with hyper-CVAD and rituximab were encouraging; 3-yr rates of CR duration (CRD) and survival (OS) were 60% and 50% overall, respectively. In younger (age < 60 years) CD20-positive subset, rates of CRD and OS were superior compared with standard hyper-CVAD (70% v 38%; P <.001% and 75% v 47%, P =.003) [Thomas D, JCO 28: 3830, 2010]. Historical experience in the adolescent and young adult (AYA) subset aged 15 – 30 yrs with CD20 positive B-lymphoblastic leukemia (now treated with pediatric augmented BFM regimen) showed that the addition of rituximab improved the 3-yr CRD rates from 26% to 65% (P =.001) and 3-yr OS rates from 47% to 75% (P =.05) compared with standard hyper-CVAD. There were no significant differences in outcome for the AYA subset by regimen (standard or modified) for the CD20 negative groups (all 3-yr rates > 70%). In contrast to the Burkitt leukemia experience, elderly pts with CD20 positive B-lymphoblastic leukemia treated with hyper-CVAD and rituximab did not benefit (rates of CRD 45% v 50%, P = NS and OS 28% v 32%, P = NS, respectively), related in part to deaths in CR. For the modified hyper-CVAD regimen (no anthracycline intensification), the rate of MRD negativity by 4- or 6-color MFC (sensitivity 0.01%, assay now 8-color MFC) at the time of CR in 95 evaluable pts was 72%. Overall, MRD positivity by MFC at the time of CR was associated with a higher relapse rate (52% v 21%, P =.01) and lower 3-yr CR duration rates (45% v 78%, P =.01). CD20 positive pts treated with rituximab had a higher rate of MRD negativity by MFC at CR than their CD20 negative counterparts (81% v 58%, P =.02). MRD positivity by MFC after hyper-CVAD and rituximab was associated with a significantly lower 3-yr CR duration rate (24% v 82%, P =.002), but survival rates were not statistically different (27% v 70%) likely due in part to deaths in CR in the older subset of the MRD-negative group. In contrast, for the CD20 negative subset, presence of detectable MRD by MFC at the time of CR did not influence 3-yr CR duration rate (58% v 63%). Additional doses of rituximab have been added to the consolidation cycles (Day 1 of cycles 5 – 8) and during the maintenance phase. Upfront dose reductions have been implemented for the induction-consolidation phase according to age and performance status in order to reduce deaths in CR. MTX-cytarabine cycles now include vincristine. All pts receive 8 IT treatments in the absence of CNS disease. Younger pts age 40 – 50 yrs receive pegylated asparginase (2000 Units/m2 with capping) during the induction-consolidation phase and early/late intensifications (augmented hyper-CVAD). Elderly pts or younger pts with B-lymphoblastic leukemia with contraindications to asparaginase are now treated with the hyper-CVAD and ofatumumab regimen regardless of CD20 expression. The cumulative experience of the serial modifications to the hyper-CVAD regimen stratified by age/MRD status and the preliminary experience with the frontline version of the augmented hyper-CVAD regimen will be presented. Disclosures:Off Label Use: Rituximab in Lymphoblastic Leukemia.

Significance of Minimal Residual Disease (MRD) by Multiparameter Flow Cytometry (MFC) In Adults with De Novo Acute Lymphoblastic Leukemia (ALL) After Therapy with the Modified Hyper-CVAD Regimen

AbstractAbstract 2145The hyper-CVAD regimen is an effective frontline program for de novo adult ALL [Kantarjian, JCO 18:547, 2000; Kantarjian, Cancer 101:2788, 2004]. Intensive cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternate with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone) interrupted with early and late intensifications. The regimen was modified in 1999 in order to improve on the results. Induction chemotherapy was administered in a laminar air flow room for pts aged 60 years or older owing to high induction mortality rate (17%). Rituximab 375 mg/m2 (days 1 & 11 of hyper-CVAD, days 1 & 8 of MTX-cytarabine for 8 total doses) was given if CD20 expression was > 20% owing to association with increased propensity for relapse [Thomas D, Blood 113:6330, 2009]. CNS prophylaxis alternated intrathecal MTX day 2 with cytarabine day 7 of the first 3 courses for low CNS risk and first 4 courses for high CNS risk (in the absence of CNS disease). The maintenance phase was extended from 24 to 30 mos with modifications of the early and late intensifications (hyper-CVAD followed by MTX-L-asparaginase mos 6 & 7 and 18 & 19) in order to reduce incidence of late relapses. Newly diagnosed or primary refractory (1 course only) pts with Philadelphia chromosome negative B-lymphoblastic leukemia (n=126) were treated with this modified hyper-CVAD regimen without anthracycline intensification (pts age 30 years or less have been allocated to treatment with the pediatric-inspired augmented Berlin-Frankfurt-Muenster regimen since 2006). Median age was 43 yrs (range, 15–83). CD20 expression was noted in 49%. Overall CR rate of the group was 93%; the rate of MRD negativity by 4- or 6-color MFC (sensitivity of 0.01%) at the time of CR in 95 evaluable pts was 72%. Overall, MRD positivity by MFC at the time of CR was associated with a higher relapse rate (52% versus 21%, p=.01) and lower 3-yr CR duration rates (45% versus 78%, p=.01). The CD20 positive pts (n=57) who were treated with rituximab had a higher rate of MRD negativity by MFC at CR than their CD20 negative counterparts (81% versus 58%, p=.02). MRD positivity by MFC after hyper-CVAD and rituximab was associated with a significantly lower 3-yr CR duration rate (24% versus 82%, p=.002), but survival rates were not statistically different (27% versus 70%) likely due in part to deaths in CR in the older subset of the MRD-negative group. In contrast, for the CD20 negative subset, presence of detectable MRD by MFC at the time of CR was not associated a with lower 3-yr CR duration rate (58% versus 63%). Dectectable MRD by MFC at the time of CR, despite subsequent eradication with consolidation chemotherapy in the majority of patients, predicts for increased risk of disease recurrence. Strategies to improve the MRD negativity rate at the time of CR (e.g., addition of monoclonal antibodies directed at other lymphoblast antigens such as CD22 for the CD20 negative subset and use of the newer anti-CD20 monoclonal antibodies for the CD20 positive subset) may further improve outcome after frontline therapy with the modified hyper-CVAD regimens. Disclosures:Thomas: Novartis: Honoraria; Bristol-Meyer-Squibb: Honoraria; Pfizer:; Amgen: Research Funding. Off Label Use: Imatinib for de novo Philadelphia positive ALL. Dasatinib for de novo Philadelphia positive ALL. Rituximab for CD20 positive ALL and Burkitt leukemia/lymphoma. Nelarabine for de novo T-lymphoblastic leukemia/lymphoma.

Outcome for Adolescents and Young Adults (AYA) with the Hyper-CVAD (with or without Rituximab) Regimens for De Novo Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma.

Abstract 3084Poster Board III-21AYAs aged 16–20 yrs with de novo ALL or LL have superior outcomes when treated with intensive pediatric regimens; event-free survival rates range from 60–70% compared to 30–40% after conventional adult chemotherapy [Stock W, Blood 112:1646, 2008]. This is in part attributed to higher dose intensity (and cumulative dose) of the anthracycline, vincristine [VCR], corticosteroid and asparaginase components. The intensive hyper-CVAD regimen (fractionated cyclophosphamide, VCR, doxorubicin, dexamethasone alternating with methotrexate and cytarabine) was originally modeled after childhood therapy for Burkitt lymphoma, and had been applied as frontline adult ALL therapy without age restriction since 1992. In contrast to conventional adult or pediatric ALL regimens, asparaginase is not administered during induction or consolidation phases. Modifications to the regimen have included the addition of rituximab for CD20 positive precursor B-cell ALL owing to adverse influence of CD20 expression, particularly in the younger subgroup [Thomas D, Blood 113:6330, 2009]. An adapted augmented Berlin-Frankfurt-Munster (BFM) regimen modeled after the CCG experience was developed specifically as frontline therapy for adolescents and adults up to age 30 in lieu of the hyper-CVAD regimen at our institution; accrual is ongoing. We updated the previous comparative hyper-CVAD experience in this young adult subset. One hundred seventy-six pts aged 13 to 30 yrs (median 22 yrs) with de novo ALL (n=149) or LL (n=27) were treated with hyper-CVAD (n=96) or modified hyper-CVAD (25 with anthracycline intensification, 55 without; 32 overall with rituximab). Eighty-three (47%) were less than 21 years of age (median 19 yrs). Forty-nine (29%) were CD20 positive. Overall complete remission (CR) rate was 97%; overall 3-yr CR duration (CRD) and survival (OS) rates were 65% and 70%, respectively. Rates for 3-yr CRD and OS were 68% and 75% if age 21 yrs or less, compared with 60% and 66%, respectively, if age 22 to 30 yrs (p=NS). The addition of rituximab improved the 3-yr CRD rates from 26% to 65% (p=.001) and 3-yr OS rates from 47% to 75% (p=.05) for the CD20 positive precursor B-cell ALL subsets, partly accounting for the improvement in outcomes. There were no significant differences in outcome by regimen for the CD20 negative subsets (all 3-yr rates > 70%). Outcomes with the hyper-CVAD regimens in AYAs appear to more closely resemble those of the pediatric approaches than the conventional regimens; incorporation of pegylated asparaginase and intensification of vincristine/corticosteroids (e.g., augmented hyper-CVAD) may further improve the efficacy of this regimen in the frontline setting. Incorporation of rituximab or the novel CD20 antibodies such as ofatumumab into the pediatric regimens warrants consideration. DisclosuresNo relevant conflicts of interest to declare.

Outcome after Frontline Therapy with the Hyper-CVAD and Imatinib Mesylate Regimen for Adults with De Novo or Minimally Treated Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL)

Historically, complete remission (CR) rates with hyper-CVAD (cyclophosphamide, vincristine [VCR], doxorubicin and dexamethasone alternating with methotrexate and cytarabine) in de novo adult Ph-ALL were 90% or better; disease recurrence remained problematic. The selective ABL tyrosine kinase inhibitor (TKI) imatinib mesylate was thus incorporated into the hyper-CVAD regimen for de novo or minimally treated Ph-ALL [Thomas, Blood 103:4396, 2004]. The final regimen included imatinib 600 mg days 1–14 of induction, 600 mg continuously with courses 2–8, followed by escalation to 800 mg as tolerated during 24 mos of maintenance therapy with monthly VCR and prednisone interrupted by 2 intensifications with hyper-CVAD and imatinib, then imatinib indefinitely. Allogeneic stem cell transplant (SCT) was performed in first CR as feasible. The study accrued from April 2001 to September 2006. Fifty-four pts with imatinib-naive de novo or minimally treated Ph-ALL were treated. Forty-five pts had active disease, untreated (n=39) or refractory (n=6) to one induction course; 9 were in CR at start. Median age was 51 yrs (range, 17–84); 52% were male, and 13% had CNS disease at presentation. Of the 45 pts with active disease, 42 (93%) achieved CR (1 CRp, 1 partial response, 1 early death from sepsis). All 6 refractory patients achieved CR. Molecular CR rate (MCR, confirmed by nested PCR) prior to SCT was 52% overall. Sixteen pts (33%) underwent allogeneic SCT in first CR within a median of 5 mos from start of therapy (range 1–13). In the de novo group, 14 pts with median age of 37 yrs underwent allogeneic SCT in first CR whereas 33 pts with a median age of 53 years did not. The 3-yr survival (OS) rates were 66% vs 49% with or without SCT, respectively, p=0.36. The 3-yr CR duration rate was 84% for pts who achieved MCR (2 of 16 had SCT) compared to 64% for those who did not (14 of 35 had SCT), p=0.1; OS rates were similar regardless of MCR status. With a median follow-up of 52 mos (range 19–83+), 22% pts relapsed within a median of 15 mos from the start of therapy (range 8–42), including 2 after allogeneic SCT without imatinib maintenance. Detection of additional chromosome abnormalities at presentation did not influence outcome. In the de novo group, 4 of 9 evaluable relapses had ABL kinase domain mutations [E459K, Y253H, Y253F, F359V], none harbored T315I. The addition of imatinib improved outcome compared with hyper-CVAD alone (irrespective of allogeneic SCT); overall 3-yr CR duration and OS rates were 68% vs 25% and 55% vs 15%, respectively, p<0.001. Incorporation of second or later generation tyrosine kinase inhibitors into the hyper-CVAD regimen may further improve on the favorable imatinib experience. Allogeneic SCT in the TKI era needs to be reexamined in a prospective randomized trial.

Prognosis and treatment of lymphoblastic lymphoma in adults: a report on 80 patients.

We analyzed prognostic factors in 80 adult patients with lymphoblastic lymphoma (LBL). Twenty-one patients received six monthly courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and maintenance chemotherapy for 12 months. The LNH-84 protocol (30 patients) consisted of four courses of high-dose CHOP followed by consolidation for 4 months. Both FRALLE (22 patients) and LALA (seven patients) protocols were two intensive chemotherapy regimens for acute lymphoblastic leukemia (ALL) that included an induction with daunorubicin, vincristine, cyclophosphamide, prednisolone (and asparaginase for the FRALLE regimen), consolidation, and maintenance chemotherapy that lasted for 2 years. Sixty-six patients (82%) achieved a complete remission (CR). The CR duration rate and overall survival rate at 30 months were estimated to be 46% and 51%, respectively, with a median follow-up of 55 months. Only two of 37 relapses occurred after 26 months. Chemotherapy protocol did not influence CR rate, CR duration, and survival. A higher CR rate was associated with an age of less than 40 years, lactic dehydrogenase (LDH) level of less than two times the upper limits of normal, and no or one extranodal site of disease. Short survival was associated with a failure to achieve CR, age older than 40 years, B symptoms, LDH level more than two times the upper limits of normal, and hemoglobin level of less than 100 g/L. Bone marrow involvement had no prognostic value. We could not evaluate precisely the prognostic value of Ann Arbor stage because inclusion criteria differed among treatment groups. Our findings suggest that age and LDH are two important pretreatment prognostic factors for adult LBL, and that the optimal prognostic staging system remains a controversial issue.