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Background: Monitoring minimal residual disease (MRD) by real-time quantitative polymerase chain reaction (RT-PCR) in chronic myeloid leukemia (CML) patients is mandatory in the era of tyrosine kinase inhibitors. Achieving a major molecular response (MMR) at 12 and 18 months predicts a better progression and event-free survival., Patients and Methods: The objective of this prospective, multicentric study was to evaluate MRD by standardized RT-PCR in 178 patients with chronic-phase CML who were treated with imatinib at different institutions in Argentina and Uruguay and to determine if achievement of a stable MMR (BCR-ABL transcript levels < 0.1%) identifies a low-risk cytogenetic relapse group. The median age of the patients was 50 years, and 55% of them had received imatinib as first-line therapy. BCR-ABL transcript levels were measured after achievement of complete cytogenetic remission (CCyR) and at 6-month intervals., Results: MMR was detected in 44% patients at the start of the study. This value increased to 79% at month 36 of evaluation. Complete molecular response (CMR) also increased from 24% to 52% of patients. Not achieving a stable MMR determined a higher risk of cytogenetic relapse (9% of MMR patients not achieving an MMR vs. 1% of patients who achieved MMR). Patients with sustained MMR had a significantly better cytogenetic relapse-free survival at 48 months (97% vs. 87%; P = .008) but showed no differences in overall survival. Patients who did not remain in CCyR changed treatment., Conclusions: A stable MMR is a strong predictor for a durable CCyR. Standardized molecular monitoring could replace cytogenetic analysis once CCyR is obtained. These results emphasize the validity and feasibility of molecular monitoring in all standardized medical centers of the world., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: Immunoglobulin D (IgD) and IgM multiple myeloma represent uncommon immunoglobulin isotypes, accounting for 2% and 0.5% of cases, respectively. Limited information is available regarding the prognosis of these isotypes, but they have been considered to have a more aggressive course than the more common immunoglobulin G (IgG) and IgA isotypes. In particular, the outcome after autologous hematopoietic stem cell transplantation (auto-HCT) has not been well defined., Patients and Methods: Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 36 patients with IgD and 11 patients with IgM myeloma among 3578 myeloma patients who received intensive therapy and auto-HCT over a 10-year period., Results: The progression-free and overall survival probabilities at 3 years were 38% (95% CI, 21%-56%) and 69% (95% CI, 51%-84%) for IgD myeloma, and 47% (95% CI, 17%-78%) and 68% (95% CI, 36%-93%), respectively, for IgM disease. Although formal statistical analysis was limited by the small sample size, these results were comparable to those for IgG and IgA patients autografted during the same time period. Transplantation-related mortality and disease relapse/progression of myeloma were also similar for all isotypes., Conclusion: This analysis demonstrates comparable outcomes in all immunoglobulin isotypes. Therefore, auto-HCT should be offered to eligible patients with IgD and IgM myeloma.

Background: Doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD) plus involved-field radiation therapy (IFRT) is the gold-standard treatment for early and advanced stages of Hodgkin lymphoma (HL). We evaluated the outcomes of patients according to prognosis at diagnosis and over time to determine who achieved complete remission (CR)., Patients and Methods: Treatment-naive patients under the age of 75 years at all stages of HL were eligible. The favorable group (FG) contained patients with stage IA-IIIA disease without bulky areas who achieved CR after the third cycle of ABVD. They received only IFRT at 25 Gy. Patients in the unfavorable group (UG) exhibited stages IIIB and IV HL. The UG also included all patients with bulky disease and the subset of the FG without CR after 3 cycles of ABVD, ie, slow responders (FGSR). The UG received 6 cycles of ABVD plus IFRT at 30 Gy to bulky areas at diagnosis or to those areas remaining positive after the third cycle of ABVD., Results: In total, 584 patients were evaluable: 285 of them belonged to the FG, and 299 to the UG. Rates of CR were 98% and 85% for the FG and the UG, respectively (P < .001). Sixty patients in the FG received 6 cycles of ABVD because they had not achieved CR after 3 cycles (ie, the FGSR subgroup). The 5-year event-free survival rate was 89% for the FG, 66% for the FGSR, and 72% for the UG (P < .001). The overall survival at 5 years was significantly better for the FG (98%) than for the FGSR (87%) and the UG (88%; P < .001)., Conclusion: Patients from the FG demonstrated excellent outcomes compared with those from the FGSR and UG, despite receiving less chemotherapy and fewer doses of IFRT.

Background: Despite several investigations, second malignancy risks (SMR) following radiotherapy alone (RT), chemotherapy alone (CT) and combined chemoradiotherapy (CRT) for Hodgkin's lymphoma (HL) remain controversial., Patients and Methods: We sought individual patient data from randomised trials comparing RT versus CRT, CT versus CRT, RT versus CT or involved-field (IF) versus extended-field (EF) RT for untreated HL. Overall SMR (including effects of salvage treatment) were compared using Peto's method., Results: Data for between 53% and 69% of patients were obtained for the four comparisons. (i) RT versus CRT (15 trials, 3343 patients): SMR were lower with CRT than with RT as initial treatment (odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.62-0.98 and P = 0.03). (ii) CT versus CRT (16 trials, 2861 patients): SMR were marginally higher with CRT than with CT as initial treatment (OR = 1.38, CI 1.00-1.89 and P = 0.05). (iii) IF-RT versus EF-RT (19 trials, 3221 patients): no significant difference in SMR (P = 0.28) although more breast cancers occurred with EF-RT (P = 0.04 and OR = 3.25)., Conclusions: Administration of CT in addition to RT as initial therapy for HL decreases overall SMR by reducing relapse and need for salvage therapy. Administration of RT additional to CT marginally increases overall SMR in advanced stages. Breast cancer risk (but not SMR in general) was substantially higher after EF-RT. Caution is needed in applying these findings to current therapies.

Myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) is increasingly used in patients with lymphoma who experience disease relapse after autologous hematopoietic stem cell transplantation (auto-HSCT) because the allograft is tumor free and may induce a graft-versus-tumor effect. We analyzed 114 patients treated with this approach from 1990 to 1999 to assess disease progression, progression-free survival (PFS), and overall survival (OS). Cumulative incidence of disease progression at 3 years was 52%, whereas treatment-related mortality was 22%, lower than previously reported. Three-year probabilities of OS and PFS were 33% and 25%, respectively. With prolonged follow-up, however, nearly all patients experienced disease progression, and 5-year probabilities were 24% and 5%, respectively. Complete remission at the time of allo-HSCT and use of total body irradiation (TBI) in patients with non-Hodgkin lymphoma (NHL) were associated with lower rates of disease progression and higher rates of OS. In summary, allo-HSCT is feasible for patients with lymphoma who have relapses after auto-HSCT and can result in prolonged survival for some, but it is usually not curative. Most likely to benefit are patients who have HLA-matched sibling donors, are in remission, and have good performance status.

In this article, we report on 904 patients undergoing transplantation for follicular lymphoma. A total of 176 (19%) received allogeneic, 131 (14%) received purged autologous, and 597 (67%) received unpurged autologous transplants. Five-year treatment-related mortality (TRM) rates were 30%, 14%, and 8% and 5-year recurrence rates were 21%, 43%, and 58% after allotransplantation, purged autotransplantation, and unpurged autotransplantation, respectively. In multivariate analyses, allotransplantation had higher TRM and lower disease recurrence. Purged autotransplantation had a 26% lower recurrence risk than unpurged autotransplantation. Five-year probabilities of survival were 51%, 62%, and 55% after allogeneic, purged autotransplantation, and unpurged autotransplantation, respectively. Advanced age, prolonged interval from diagnosis to transplantation, high lactate dehydrogenase (LDH), refractory disease, bone marrow involvement, low performance scores, and transplantation between 1990 and 1993 were associated with adverse outcomes. Total body irradiation was associated with higher TRM but lower recurrence. There was no association between acute or chronic graft-versus-host disease and recurrence after allotransplantation. We conclude that both allogeneic and autologous transplantation can induce durable remissions. There may be a benefit to graft purging in autologous transplantation. The decreased recurrence after allotransplantation is offset by increased TRM. We did not detect a correlation between graft-versus-host disease (GVHD) and recurrence. Finally, outcomes of transplantation for follicular lymphoma show improvement over the past decade.

Lymphoblastic lymphoma (LBL) is a rare, clinically aggressive neoplasm of the young that frequently involves the bone marrow (BM) and/or central nervous system. Because LBL is similar to acute lymphoblastic leukemia, some centers prefer allogeneic hematopoietic stem cell (SC) transplantation to autologous SC transplantation. We retrospectively analyzed outcomes for patients who underwent autologous (auto, n = 128) or HLA-identical sibling (allo, n = 76) SC transplantations from 1989 to 1998 and were reported to International Bone Marrow Transplant Registry (IBMTR) or Autologous Blood and Marrow Transplant Registry (ABMTR). Allo stem cell transplant (SCT) recipients had higher treatment-related mortality (TRM) at 6 months (18% versus 3%, P =.002), and this disadvantage persisted at 1 and 5 years. Early relapse rates after alloSC transplantation and autoSC transplantation were similar, but significantly lower relapse rates were observed in alloSCT recipients at 1 and 5 years (32% versus 46%, P =.05; and 34% versus 56%, P =.004, respectively). No differences were noted in lymphoma-free survival rates between alloSC transplantations and autoSC transplantations (5-year rates 36% versus 39%, P =.82). AutoSCT recipients had higher overall survival at 6 months (75% versus 59%, P =.01), but survival did not significantly differ between the 2 groups at 1 and 5 years (60% versus 49%, P =.09; 44% versus 39%, P =.47, respectively). Multivariate analyses to account for confounding factors confirmed these results. Independent of SCT type, BM involvement at the time of transplantation and disease status more advanced than first complete remission were associated with inferior outcomes. In summary, alloSC transplantation for LBL is associated with fewer relapses than with autoSC transplantation, but higher TRM offsets any potential survival benefit.

Background: The aim of this study was to increase disease-free survival (DFS) in AML in CR1 using a high-dose cytarabine consolidation plus G-CSF as in vivo purging and mobilization of CD34+ cells before ablative therapy and peripheral blood autograft., Patients and Methods: Fifty-six consecutive AML patients (pts) (including 11 children < 15 years), with a median age of 32 years, were analyzed. After achievement of CR with cytarabine-mitoxantrone (7 + 3) in adults and a BFM-like protocol in children, pts were intensified with cytarabine 2 g/m2 x six doses plus mitoxantrone for adults, or, 3 g/m2 x six doses plus etoposide for children, followed by G-CSF 5 micrograms/kg SC daily. The ablative regimens used were busulfan and cyclophosphamide (Bu/Cy) in standard-risk pts plus etoposide (2400 mg/m2) for high-risk pts., Results: For the 54 pts who underwent autologous transplant, the median time to reach > 1.0 x 10(9)/l neutrophils was 13 days (8-48), and to reach platelets > 25 x 10(9)/l 32 days (8-364), and the median numbers of red blood cell and platelet units transfused were 3 and 5, respectively. Six pts had treatment-related deaths (11%). The disease-free survival and overall survival at 30 months (mos) for the 56 eligible pts were 61% and 62%, respectively. Only two relapses were observed after 21 mos, while there were 12 relapses within 12 mos., Conclusions: The above treatment results in a similar DFS rate as does rescue with bone marrow cells, with faster neutrophil and platelet recovery.

Objective: To evaluate in a multivariate analysis the prognostic factors associated with hematopoietic recovery and the supportive care requirements after autotransplant of progenitor cells (PC) from various sources: bone marrow (BMPC), BMPC & peripheral blood (PBPC), and PBPC alone., Patients and Methods: A total of 570 patients with hematological malignancies and solid tumors underwent high-dose therapy followed by autotransplant. PBPC were obtained after mobilization with chemotherapy and/or cytokines. One-hundred five patients received BMPC, 217 received BMPC & PBPC and 248 PBPC alone; all of the patients received G-CSF or GM-CSF after infusion., Results: In a multivariate analysis the recovery of neutrophils was adversely associated with low numbers of nucleated cells infused (P < 0.13), bone marrow progenitor cell source, and diagnosis of multiple myeloma and acute leukemia (P < 0.001). The factors that adversely affected platelet recovery were low number of nucleated cells and diagnosis of multiple myeloma and acute leukemia (P < 0.001)., Conclusions: We conclude that BMPC adversely affect neutrophil recovery while low numbers of nucleated cells and diagnosis of multiple myeloma and acute leukemia adversely affect both neutrophil and platelet recovery.

A total of 151 patients with previously untreated Hodgkin's disease, clinical stages III-IV A & B, were randomized to receive CVPP for 6 cycles, or CVPP plus RT 3000 cGy to previously involved areas between the 3rd and 4th cycles. CVPP consists of cyclophosphamide 600 mg/m2/i.v., vinblastine 6 mg/m2/i.v. on day 1, procarbazine 100 mg/m2/p.o. and prednisone 40 mg/m2/p.o. on days 1 to 14. Both groups displayed similar clinical characteristics at diagnosis. Sixty-six were treated with CVPP + RT (52 St III and 14 St IV) and 85 with CVPP alone (68 St III and 17 St IV). Complete remission was obtained in 57 (86%) of 66 patients who received CVPP plus RT, and in 62 (73%) of 85 patients treated with CVPP. Five and sixteen patients, respectively, achieved partial responses, while 2 in each group died during treatment. At 7 years, duration of complete remission and failure-free survival were: 51% and 45% for those treated with CVPP plus RT, and 23% and 21% with CVPP alone (p = 0.0150 and P = 0.0016, respectively). Overall survival at 7 years was 71% and 58%, respectively (p = 0.1488). A dose analysis performed in 84 pts showed that 91% and 88% received full protocol doses of CPM and PCZ, respectively, in the CVPP + RT group, and 95% and 94% for CVPP. The WBC nadir was 3.5 and 3.7 x mm3, respectively. Of 25 pts on CVPP + RT who relapsed, 9 are now disease-free, 5 are alive with disease and 11 have died, and with CVPP, of 37 relapsing pts, 18 are disease-free, 5 are alive with disease and 14 are dead.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized multicenter phase III study was conducted to compare the efficacy and toxicity of CHOP and CNOP in intermediate and high-grade non-Hodgkin's lymphoma. CHOP consisted of cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, doxorubicin 50 mg/m2 on day 1 and prednisone 50 mg/m2 on days 1 to 5. The CNOP regimen was identical to CHOP except for replacement of doxorubicin by 10 mg/m2 mitoxantrone. Patient characteristics were evenly distributed in the two arms, except for age and stage, which slightly favoured the CHOP arm. The rate of complete remission was 70% (31/44) in patients treated with CHOP and 51% (23/45) in those receiving CNOP (P = 0.09). At 48 months and with a median follow-up of 41 months, 44% of the complete responders treated with CHOP and 64% of those treated with CNOP were estimated to still be in their first complete remission (P = 0.14), while 31% and 34% remained alive and free of progression. The Kaplan-Meier estimate of overall survival at 48 months is 53% and 50%, respectively. The higher response rate obtained with CHOP probably reflected a less aggressive lymphoma population. The mean WBC nadir was 2.0 x 10(9)/l for CHOP and 1.8 x 10(9)/l for CNOP. One and three patients, respectively, died during induction. Nausea, vomiting and cardiac toxicity were similar. More alopecia and mucositis were observed with CHOP. We conclude that CHOP and CNOP have similar toxicities and are equivalent in previously untreated non-Hodgkin's lymphoma in terms of complete response rate, event-free survival and overall survival.

This study tested the efficacy of rubidazone and cytosine arabinoside in 35 patients (13 children and 22 adults) with acute myelocytic leukemia in first relapse. Induction consisted of 1-2 courses of rubidazone 200 mg/m2 days x 4 days plus cytosine arabinoside 100 mg/m2 x 7 days in CI followed by 2 consolidation courses of 3 days and 5 days. Nineteen patients (54%) achieved complete remission, 8 failed to respond, and 8 died. Twelve patients relapsed after 1 to 9 months, at a median of 4 months, 1 patient died of cardiac failure and 1 remains in complete remission at 12 months. Five patients underwent bone marrow transplantation, 3 of them autologous, 1 was still in complete remission at 29 months, 1 relapsed, and 1 died of sepsis. Two received allogeneic marrow transplants and died at 3 and 4 months afterwards of VOD and graft failure. The main toxicity was severe and prolonged myelosuppression.

Two consecutive studies for adult patients with acute lymphoblastic leukemia without previous treatment were analyzed and compared. Protocol ALL-79 included 137 patients treated with a 'standard therapy' consisting of prednisone, vincristine and daunomycin as induction, CNS prophylaxis with IT chemotherapy and maintenance with 6-mercaptopurine, methotrexate and pulses with vincristine and prednisone. Protocol ALL-82 included 145 patients treated with an 'intensive therapy' consisting of 8 weeks of induction with vincristine, prednisone, daunomycin and L-asparaginase, followed by 6-mercaptopurine, cyclophosphamide and cytosine arabinoside. At 3 months after induction, a 6-week consolidation therapy was given, with vincristine, adriamycin, dexamethasone and L-asparaginase, followed by cyclophosphamide, cytosine arabinoside and 6-mercaptopurine. Rates of complete remission were 80% and 78% for protocols ALL-79 and ALL-82 respectively. The probability of remaining in complete remission at 80 months was 20% and 34%, respectively (p = 0.0014). Median survival for protocol ALL-79 was 14 months, and 34 months for protocol ALL-82; at 80 months the probability of survival is 22% and 35% for the two protocols (P = 0.0024). In protocol ALL-82, the probability of remaining in CR for favorable prognosis patients (age = less than 35 years and WBC = less than 50.000) is 56% at 80 months, and only 8% at 50 months for the unfavorable group (age greater than 35 and/or WBC greater than 50.000) (P = 0.0012). The probability of survival was statistically superior in patients with favorable prognoses, with 54% of them still alive at 60 months compared to only 13% of patients with unfavorable prognoses (P = 0.0085).(ABSTRACT TRUNCATED AT 250 WORDS)

In acute lymphoblastic leukemia (ALL), central nervous system (CNS) prophylaxis with cranial irradiation plus 5 doses of intrathecal methotrexate (i.t. MTX) reduces the incidence of CNS relapse to 7%-15%. However, increased evidence of CNS delayed toxicity started to be recognized as CT scan abnormalities and neuropsychologic alterations, mainly in children. Two questions were analyzed in the present report: (1) Will further doses of i.t. methotrexate and dexamethasone (i.t. MTX-DMT) decrease the incidence of CNS relapse in patients treated early in remission with cranium irradiation plus i.t. MTX-DMT even more? (2) Is i.t. MTX-DMT given during induction and maintenance equally as effective as cranium irradiation plus i.t. MTX-DMT? A randomized study was designed to answer the first question. Incidence of primary CNS relapse in i.t. MTX-DMT-treated patients with a WBC count less than 50,000 was 11% (15 of 135 patients) and was 11% (17 of 150) in the untreated group. In patients with a WBC count greater than 50,000, it was 16% (6/37) in the treated group and 19% (6/31) in the control group. No difference was observed according to treatment in both prognostic groups. Patients in this study were retrospectively compared with a consecutive protocol in which patients received 3 doses of i.t. MTX-DMT alone during induction plus 3 doses weekly during the first month of remission and every 3 mo thereafter. The incidence of primary CNS leukemia at 60 mo in patients with a WBC count less than 50,000 was 20% in the irradiated group and 32% in the group with i.t. MTX-DMT alone. This difference was not significant. However, the relapse-free survival at 60 mo was 26% and 41%, respectively, (p less than 0.0005). The incidence of primary CNS relapse in patients with a WBC count more than 50,000 at 48 mo was 28% in the irradiated group and 42% in the nonirradiated group. The difference was not significant. The duration of complete remission was similar, remaining at 15% and 16% of patients disease-free at 48 mo, respectively. We conclude that (A) after cranial irradiation plus i.t. MTX-DMT X 5, the use of additional doses of i.t. MTX-DMT is not of further benefit in preventing CNS relapse; (B) the use of i.t. MTX-DMT alone compares similarly with cranial irradiation plus i.t. MTX-DMT in the incidence of CNS relapse; and (C) relapse-free survival and survival in patients with a WBC count less than 50,000 were significantly longer in those without cranial irradiation.