[Impact on renal function of an early switch from conventional to liposomal amphotericin B formulation in the empirical treatment of fungal infections]. / Impact sur la fonction rénale d'un relais précoce de la formulation conventionnelle de l'amphotéricine B par sa formulation liposomale dans le cadre d'un traitement empirique antifongique (Etude Nephemat).

OBJECTIVE: The authors had for aim to define the threshold of nephrotoxicity before switching to other antifungal treatment in hematological patients treated by conventional amphotericin B (AmB) as an empiric antifungal treatment. DESIGN: A prospective randomised multicenter study was made on 32 neutropenic hematological patients receiving conventional AmB for empirical antifungal treatment. The patients were randomised after a greater than or equal to 30% increase of serum creatinine (sCr). Patients in the early-switch group received liposomal AmB just after randomisation and patients in the late-switch group received liposomal AmB only when serum creatinine increase was greater or equal to 100% or sCr reached 170mumol/L. RESULTS: Thirty-one patients were analysed: 16 patients in the early-switch group and 15 patients in the late-switch group (seven switched to liposomal AmB and eight continued conventional AmB treatment). The mean age of patients was 48 years and 68% were men. The most frequent underlying haematological malignancy was acute leukemia (94%). In the late-switch group, the degradation of renal function continued after randomisation contrary to the early-switch group: median variations of calculated sCr clearance in early- and late-switch groups were -16.8 and -1.5%, respectively (P=0.03). Moreover, an early switch was cost-effective with a sCr lower duration of hospitalisation in comparison with a late switch. CONCLUSIONS: This randomised trial suggests that an early switch to Liposomal AmB improves and preserves renal function in comparison with a late switch.

High-dose imatinib mesylate combined with vincristine and dexamethasone (DIV regimen) as induction therapy in patients with resistant Philadelphia-positive acute lymphoblastic leukemia and lymphoid blast crisis of chronic myeloid leukemia.

Imatinib combined with high-dose chemotherapy is now becoming the gold standard for treatment of Philadelphia chromosome-positive acute leukemias. However, in all studies imatinib dosage was tapered to 400-600 mg per day. We decided to initiate a clinical trial to evaluate an opposite strategy based on high-dose imatinib (800 mg per day) combined with a less intensive chemotherapeutic regimen (vincristine and dexamethasone), which we called the DIV induction regimen. Thirty-one patients (18 relapsing or refractory Ph+ acute lymphoblastic leukemias and 13 lymphoid blast crisis chronic myelogenous leukemias) were enrolled. Complete remission (CR) was obtained in 28 out of 30 assessable patients. The median bcr-abl/abl ratio after the induction course was 0.1%. Median time to neutrophil recovery was 21 days. Fungus infections were observed in six patients out of 31 and possibly related to dexamethasone. Neuropathy due to vincristine was noted in 14 cases. Nine out of 19 patients under 55 years received allogenic stem cell transplantation after a median time of 78 days post-CR. Patients older than 55 years experienced a 90% CR rate without additional toxicities, suggesting the DIV regimen may also be proposed as a front line therapy in older patients.

Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study.

Adult patients with acute lymphoblastic leukemia (ALL) and t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4 have a poor outcome. We have evaluated the impact of an intensified post-remission therapy using a high-dose chemotherapy course followed by allogeneic or autologous SCT on the outcome of 58 patients with t(1;19)/E2A-PBX1 (E2A group, n=24) or t(4;11)/MLL-AF4 (MLL group, n=34) treated in the LALA-94 multicenter prospective study. Patients in the MLL group had higher WBC counts and more frequent DIC. CR rates achieved by MLL and E2A groups were similar to other B-cell ALL (87, 82 and 86% respectively). While in CR, patients with a donor were assigned to alloSCT (n=22), the remaining patients with were randomized between autoSCT (n=15) or chemotherapy (n=8). Five-year overall survival was 31 and 45% for E2A and MLL groups, respectively. In both groups, DFS was higher in the alloSCT arm as compared to autoSCT and chemotherapy arms. The results of this study show that chemotherapy intensification did not overcome the poor prognosis of adults with t(1;19)/E2A-PBX1. Allogeneic SCT should thus be offered in first CR to patients with t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4. New therapeutic approaches are needed for patients without donor.

Remission induction chemotherapy induces in vivo caspase-dependent apoptosis in bone marrow acute myeloid leukemia blast cells and spares lymphocytes.

BACKGROUND: The goal of new therapeutic strategies is to adapt the treatment of acute myeloid leukemia (AML) patients to the prognostic and/or to the hematological response. METHODS: We analyzed in vivo apoptosis induction in blast cells and in lymphocytes of AML patients receiving remission induction treatment. RESULTS: We show, on 12 peripheral blood samples, that the increase of peripheral apoptotic blast cells cannot be considered as the earliest marker of the treatment efficiency, because the significant increase of apoptosis followed the white blood cell and the peripheral blast cell count reductions, probably due to an efficient clearance of circulating apoptotic cells. Furthermore, the study of 65 bone marrow samples at d15 showed that the treatment induced apoptosis of blast cells while sparing the lymphocytes. This apoptosis was evidenced both at the caspase and at the membrane levels using respectively fmk-VAD-FITC and Annexin V binding assays. We found that less than 50% of apoptosis, measured with the fmk-VAD-FITC, in the d15 residual bone marrow blast cells, correlated with lower disease-free survival probability. CONCLUSION: More studies are needed in larger series and earlier during the remission induction treatment to confirm the possible prognostic significance of in vivo apoptosis induction.

Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group.

Internal tandem duplications (ITDs) of the FLT3 gene have been observed in about 35% of APL cases. If FLT3-ITD is associated with a worse outcome in patients with acute myeloid leukemia (AML) in general, its prognostic value in acute promyelocytic leukemia (APL) is still a matter of debate. We investigated incidence, associated clinical features, and prognostic implication of FLT3-ITD, but also FLT3-D835 point mutation and N-Ras or K-Ras mutations in 119 APL patients, all prospectively enrolled in the two consecutive APL-93 and APL-2000 trials. Mutation incidences were 38, 20, and 4%, for FLT3-ITD, FLT3-D835, and Ras, respectively. The presence of FLT3-ITD was associated with high white blood cell count, high Sanz index, M3-variant subtype, and V/S PML-RAR alpha isoforms. Complete remission (CR), induction death, and death in CR rates were not affected by FLT3 or Ras mutations, as well as cumulative incidence of relapse. However, a trend for a shorter overall survival (P=0.09) was observed in FLT3-ITD patients, because of a very poor postrelapse survival (P=0.02). This feature, which has been also reported in patients with AML in general, is suggestive of an underlying genetic instability in FLT3-ITD patients, leading to the acquisition of additional unknown bad-prognosis gene mutations at relapse.

Follow-up of complete cytogenetic remission in patients with chronic myeloid leukemia after cessation of interferon alfa.

PURPOSE: A small proportion of patients with chronic myeloid leukemia (CML) achieve a complete cytogenetic response (CCR), defined as the disappearance of Philadelphia (Ph) chromosome-positive metaphases, after treatment with interferon alfa (IFN). In this population of patients, the question of whether treatment should then be withdrawn is not yet resolved. PATIENTS AND METHODS: In the present study, we followed 15 patients who stopped IFN after achieving CCR. In nine patients IFN was stopped in view of adverse reactions (n = 8) or patient's choice (n = 1). For the remaining six patients, the treatment was stopped because no BCR/ABL rearrangement could be detected by reverse transcriptase polymerase chain reaction (RT-PCR) in four successive analyses using peripheral-blood samples. RESULTS: Loss of CCR and survival were not statistically different (P =.48; P =.7) for the 15 patients who stopped IFN compared with 41 other CCR patients who continued IFN therapy in our institution. The median follow-up after discontinuation of IFN treatment was 36 months (range, 6 to 108 months). Seven patients (47%) (females, or CCR > 24 months and RT-PCR negative before IFN cessation; P <.0001) did not relapse. Eight other patients (53%) relapsed (lost CCR) within 3 to 33 months of treatment discontinuation. One of them relapsed in major cytogenetic remission (MCR) and was still in MCR 87 months after stopping therapy without any treatment. CONCLUSION: It is possible to stop IFN treatment at least in some patients with CML who achieve a prolonged period of CCR. This study also illustrates the hypothesis that persistence of low numbers of Ph-positive cells does not necessarily imply hematologic relapse.

Allogeneic hematopoietic stem-cell transplantation after nonmyeloablative preparative regimens: impact of pretransplantation and posttransplantation factors on outcome.

PURPOSE: To analyze the impact of pre- and posttransplantation factors on the outcome of allogeneic transplantation after nonmyeloablative conditioning regimens. PATIENTS AND METHODS: Ninety-two allogeneic transplantations after nonmyeloablative preparative regimens were reported to the Société Française de Greffe de Moelle Registry registry. Initial diagnoses were lymphoid diseases (n = 22), myeloma (n = 14), acute leukemia and myelodysplasia (n = 41), chronic myelogenous leukemia (n = 12), and solid tumors (n = 3). Forty-six patients had previously received a transplant, and 49 had progressive disease before transplantation. Three types of conditioning regimens were used with fludarabine or antithymocyte globulins. Eighty-nine patients underwent transplantation, 60 from peripheral-blood progenitor cells. Eighty-six patients received graft-versus-host disease (GHVD) prophylaxis for a median duration of 53 days. RESULTS: Seventy-nine patients engrafted, with 40 complete and 21 mixed chimerisms. The acute GHVD rate at 3 months was 50% +/- 11%. Fifty-two patients achieved complete remission and 12, partial remission. At 18 months after transplantation, the overall survival (OS) and the transplant-related mortality (TRM) were 32% +/- 12% and 38% +/- 14%, respectively. Initial diagnosis and disease status before transplantation significantly influenced survival. Age and GHVD prophylaxis type significantly influenced TRM. We also showed an impact of GHVD prophylaxis duration on OS and TRM. In multivariate analysis, three factors remained of prognostic value on OS: initial diagnosis, disease status at transplantation, and GHVD prophylaxis duration. CONCLUSION: This series shows encouraging results from nonmyeloablative conditioning regimens before allotransplantation and demonstrates the impact of some pre- and posttransplantation factors on outcome after transplantation.

Autologous or allogeneic stem cell transplantation as post-remission therapy in refractory or relapsed acute myeloid leukemia after highly intensive chemotherapy.

Post-remission options were compared in a population of 262 relapsing and refractory acute myeloid leukemia patients achieving complete remission (CR) after the same re-induction according to etoposide - mitoxantrone - cytarabine (EMA) trials. The selection of post-remission therapy depended on trial recommendations, age, performance status, and availability of an HLA-identical sibling. One hundred and thirty patients received chemotherapy consolidation courses, 50 received autologous stem cell transplantation (SCT), and 43 underwent allogeneic bone marrow transplantation (BMT), while 39 did not receive any additional therapy. The preliminary analysis identified 3 favorable prognostic factors correlated with event-free survival (EFS): M3 subtype, previous CR duration > 1 year, and transplantation. Three year EFS was 68 vs. 23% with autologous SCT and allogeneic BMT in M3 patients and, respectively, 41 vs. 20% in non-M3 patients. Three year probabilities of treatment-related mortality were 11 and 47%, respectively. A statistical model was conceived with adjustment on prognostic factors and post-remission option. In the multivariate analysis, autologous SCT appeared significantly better than allogeneic BMT (P < 0.01) or chemotherapy (P = 0.001), while allogeneic BMT was not statistically different than chemotherapy. This indicates a high treatment-related toxicity with allogeneic BMT in patients re-induced by highly intensive chemotherapy, and therefore a tendency for a better outcome with autologous SCT as post-remission treatment in those patients.

Response to recombinant interferon alpha in patients with chronic myelogenous leukemia in a single center: results and analysis of predictive factors.

To improve the management of chronic myeloid leukemia (CML) in a single center, we used interferon alpha (IFN alpha) to treat newly diagnosed CML patients and investigated the factors predictive of a major cytogenetic response. Fifty-two patients (pts) with a median age of 51.5 years (16-68), were given interferon alpha (IFN alpha) (5 millions/m2/day, subcutaneously). The median interval between diagnosis and IFN alpha was 41.5 days (0-160). The doses of INF alpha were adjusted to maintain the white blood cell (WBC) count between 1.5 and 5 x 10(9)/l and the platelet count between 50 and 100 x 10(9)/l. At diagnosis, Sokal's criteria were used to classify patients into three groups: low (n = 24), intermediate (n = 19) and high risk (n = 9). A complete hematological response (CHR) was achieved in 42 cases (80.7%). A partial response was present in nine; only one patient did not respond. By multivariate logistic regression analysis, only the age at diagnosis was found to influence the CHR rate (P = 0.06). Cytogenetic response was evaluated in 46 responder patients. Twenty-three patients achieved a major cytogenetic response (MCR) which was either partial ( > or = 65% pH negative cells) (n = 3) or complete (CCR) (n = 20). By univariate analysis, two disease-related variables were found to influence the MCR rate in 40 evaluable CHR patients: spleen size at diagnosis and peripheral blood blast percentage. However, using either univariate or multivariate analysis, the most significant factor was the achievement of CHR within 3 months (P < 0.0004 and P < 0.0002, respectively). These results show that IFN alpha can induce high rates of hematological and cytogenetic responses when administered in doses leading to myelosuppression. The achievement of CHR within 3 months could be useful to identify early, those patients who will not respond to IFN alpha and who need alternative treatments such as allogeneic or autologous stem cell transplantation.

Factors affecting both peripheral blood progenitor cell mobilization and hematopoietic recovery following autologous blood progenitor cell transplantation in multiple myeloma patients: a monocentric study.

The aim of the study was to analyze the factors influencing peripheral blood progenitor cell (PBPC) collection after high-dose cyclophosphamide (HDCYC) (7 g/m2) and hematopoietic recovery after autologous transplantation of HDCYC-mobilized PBPC (ABPCT) in 116 patients with aggressive multiple myeloma (MM). Following HDCYC 74 patients received hematopoietic growth factors (HGF), either G-CSF (n = 19) or GM-CSF (n = 55). All the patients were subsequently planned to undergo ABPCT. PBPC collection was possible for 106 patients. The most important prognostic factor for collection of more than 25 x 10(4) CFU-GM cells/kg and 2 x 10(6) CD34+ cells/kg was the use of HGF (P = 0.002 and 0.009, respectively). Previous use of an alkylating agent, response to treatment before HDCYC, and interval between diagnosis and HDCYC were also significant factors (P = 0.004, 0.025 and 0.001, respectively). The number of CFU-GM cells infused was the most important parameter for rapid and complete hematological recovery after ABPCT (P < 0.0001). Thus the use of HGF post-HDCYC is the major factor which, associated with reduced time between diagnosis and HDCYC and the use of an alkylating agent, could increase the numbers of hematopoietic progenitors collected, and subsequently improve hematopoietic recovery following ABPCT in MM patients.

Treatment of relapsing acute promyelocytic leukemia by all-trans retinoic acid therapy followed by timed sequential chemotherapy and stem cell transplantation. APL Study Group. Acute promyelocytic leukemia.

The purpose of this study was to assess the safety and efficacy of stem cell transplantation (SCT) mainly autologous SCT as consolidation therapy in APL patients who relapsed and achieved a second complete remission (CR2). Fifty adult patients with a first relapsed APL, of whom 39 had been previously treated with ATRA, entered a multicenter trial of oral ATRA until complete remission (CR) achievement followed by timed sequential chemotherapy (EMA combining etoposide 200 mg/m2/day for 3 days, mitoxantrone 12 mg/m2/day for 3 days, and cytarabine 500 mg/m2/day for two sequences of 3 days). EMA was started either after CR achievement, or on day 1 of ATRA because of initial white blood cell (WBC) counts >5 x 10(9)/l, or rapidly added to ATRA in order to prevent ATRA syndrome because WBC count increased under ATRA. Forty-five patients (90%, 95% CI 78%-97%) were in CR after induction therapy. Five patients died from infection during aplasia following EMA chemotherapy. Eleven patients who achieved CR had a familial HLA-identical donor and were allografted. The median disease-free survival (DFS) of allografted patients was 8.2 months. The 34 other CR patients were scheduled for autologous peripheral blood (PB) SCT (intent-to-treat group). Actually, autologous transplantation was only carried out in 22 patients (65%) (17 PBSCT and five autologous bone marrow transplantation (BMT)). Reasons for not autografting were early relapse (three patients), severe toxicity of EMA chemotherapy (six patients), and refusal or failure of stem cell harvest (three patients). The 3-year DFS rate of patients actually autografted was 77%. Among the 17 autografted patients still in CR2, nine patients have already reached a longer CR2 than first CR (CR1). Results of detection of PML/RARalpha by RT-PCR after autologous transplantation show negative findings in eight of the nine patients tested. We conclude that (1) ATRA combined to EMA chemotherapy is effective in the treatment of relapsed APL; (2) allogeneic BMT may be too toxic after salvage treatment including EMA intensive chemotherapy; (3) clinical outcome of autografted patients and preliminary molecular results regarding detection of PML/RARalpha after autologous PBSCT are encouraging.

5-Fluorouracil-resistant CD34+ cell population from peripheral blood of CML patients contains BCR-ABL-negative progenitor cells.

Despite the marked expansion of leukemic cells observed in the hematopoietic system of chronic myeloid leukemia (CML) patients, there is clinical and experimental evidence that normal nonclonal cells persist in the bone marrow (BM) and peripheral blood (PB) of patients in the early chronic phase. In this study, we attempt to select the benign progenitor-enriched population from the PB of CML patients. The CD34+ cells isolated from the PB of 12 CML patients in the chronic phase were treated with low doses (5 or 10 micrograms/mL) of 5-fluorouracil (5-FU). We expanded these cells for 7 days in liquid cytokine-mediated cultures. This expansion in the presence of interleukin-1 (IL-1) plus stem cell factor (SCF) plus IL-3 or leukemia inhibitory factor (LIF) plus SCF plus IL-3 seemed at least to preserve the initial clonogenic potential of CD34+ and 5-FU-resistant CD34+ cells. For the presence of BCR-ABL, mRNA from each of the 12 patients was studied by reverse-transcriptase-polymerase chain reaction (RT-PCR) on 10-15 pooled CFU-GM colonies plucked from methylcellulose cultures of starting and expanded populations. Although all PCR results were positive for colonies harvested before liquid culture, we were able to identify BCR-ABL-negative colonies from an expanded CD34+ population cultured in the presence of recombinant cytokines in 11 of 12 patients studied. 5-FU pretreatment of CML CD34+ cells markedly reduced their clonogenic potential and growth factor-mediated cell proliferation but favored higher frequency of BCR-ABL-free colonies. In conclusion, these data show that 5-FU-resistant CD34+ cells from the PB of CML patients contain normal progenitor cells, which can be selected and expanded in short-term cytokine-mediated cultures.

Inhibition of chronic myelogenous leukemia cells harboring a BCR-ABL B3A2 junction by antisense oligonucleotides targeted at the B2A2 junction.

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the BCR-ABL hybrid gene. Two types of hybrid BCR-ABL mRNA have been found, B2A2 and B3A2. As the BCR-ABL rearrangement is specific to leukemic cells, selective inhibition of leukemic cell growth by BCR-ABL antisense oligonucleotides (ASO) has been reported in vitro for CML patients and cell lines. However, controversial results have been obtained from preclinical studies using anti-BCR-ABL ASO, as nonspecific inhibition of leukemic cell growth was evidenced in some cases. B3 exon secondary structure was deduced from its sequence and found to be a loop. According to this predictive structure of exon B3, a 56-mer antisense oligonucleotide targeting the polypurine bases from the B2A2 junction was devised which would inhibit proliferation (MTT assay) of B3A2 junction cell lines (K562 and a murine cell line Ba/F3 transfected with the B3A2 junctional sequence). This ASO had a hairpin-like secondary structure and was found to be much more resistant to the action of nucleases than control 18-mer standard oligonucleotides. Hybridization to its target mRNA occurs via formation of a triplex structure. A concentration of 5 microM of specific 56-mer B2A2 ASO was necessary to demonstrate 50% optical density (OD) reduction for K562 cell line and Ba/F3 transformed by B3A2 cDNA. Sense and non-sense 56-mer sequence or 18-mer linear ASO showed no effect for these concentrations. Western blot showed a partial inhibition of P210 protein; expression of P145abl remains unchanged. The 56-mer ASO also inhibited the proliferation of B2A2 junction cell line BV173 at the same concentration and showed no effect on the HL60 cell line used as control.

Outcome of allogeneic hematopoietic stem-cell transplantation for adult patients with AML and 11q23/MLL rearrangement (MLL-r AML).

Acute myeloid leukemia (AML) with 11q23/MLL rearrangement (MLL-r AML) is allocated to the intermediate- or high-risk cytogenetic prognostic category depending on the MLL fusion partner. A more favorable outcome has been reported in patients receiving an allogeneic hematopoietic stem-cell transplantation (alloHSCT), but this has not been confirmed in large series. We analyzed the outcome of alloHSCT among adult patients reported to the Acute Leukemia Working Party between 2000 and 2010. We identified 159 patients with 11q23/MLL rearranged AML allografted in first complete remission (CR1, n=138) or CR2, mostly corresponding to t(9;11), t(11;19), t(6;11) and t(10;11) translocations. Two-year overall survival (OS), leukemia-free survival (LFS), relapse incidence and non-relapse mortality were 56±4%, 51±4%, 31±3% and 17±4%, respectively. The outcome differed according to 11q23/MLL rearrangement, being more favorable in patients with t(9;11) and t(11;19) compared with t(10;11) and t(6;11) (2-year OS: 64±6% and 73±10% vs 40±13% and 24±11%, respectively; P<0.0001). Multivariate analysis for OS identified t(6;11), t(10;11), age>40 years and CR2 as unfavorable features, whereas t(6;11), t(10;11), CR2 and the use of reduced-intensity conditioning regimen affected poorly the LFS. This study confirms the potential role of alloHSCT for adult patients with 11q23/MLL rearranged AML in CR1.

Treatment of hematological malignancies relapsing after allogeneic bone marrow transplantation.

The rate of relapse after allogeneic bone marrow transplantation (BMT) varies between 15 and 60%. New therapeutic strategies are required urgently as no significant results have been obtained with standard chemotherapy. The best results of second allogeneic BMT have been obtained when the interval between the first and the second transplant was more than 6 to 20 months, depending on the study. Veno-occlusive disease was an important cause of non-leukemic death (13-65%). As the toxicity of second BMT is very high, other treatments have been considered: complete remissions were reported after sudden discontinuation of the immunosuppressive therapy. Interferon-alpha has been used for chronic myeloid leukemia patients and may achieve hematological and cytogenetic complete remission. More recently, donor leucocytes transfusions have been proposed and at least in some cases, have led to molecular complete remission (polymerase chain reaction with double amplification) in chronic myeloid leukemia patients. However, non predictable marrow aplasias and graft-versus-host reactions hamper the efficacy of this strategy. Finally, hemopoietic growth factors used to promote donor cell growth produce interesting results which deserve further studies.

Recombinant alpha-interferon as treatment for chronic myelogenous leukemia in relapse after allogeneic bone marrow transplantation: a report from the Société Française de Greffe de Moelle.

Thirty three patients with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) in relapse after allogenic bone marrow transplantation (BMT) were treated with recombinant alpha-interferon (IFN). Ten patients received IFN for cytogenetic relapse (group I) and 23 (group II) for hematologic relapse. The starting dose of IFN varied from 1.7 to 6 million units/m2/day (median 3 x 10(6) U/m2/day). Among the 10 group I patients, 3 subsequently developed hematologic relapse. Of the other 7, a cytogenetic response was observed in 6 (complete 4, minor 2). Three of these responders are alive in complete cytogenetic remission. Of the 23 group II patients, 3 did not respond to IFN but 20 achieved a complete (CHR) (n = 14) or a partial hematologic response (PHR) (n = 6). Thirteen of the 14 CHR patients subsequently achieved a cytogenetic response (complete 7, minor 6). Seven of the latter 13 patients are still alive in complete cytogenetic remission (CCR). Thus, for the entire group of 33 patients, IFN was followed by CCR in 11 cases (33%); all these patients are still alive and the median follow-up in CCR is now 60.7 months (range 35.3-72.5 months). The BCR-ABL rearrangement was not detected by RT-PCR in 5 of the 10 patients analyzed. Eleven other patients developed either blast crisis or acceleration. The 3-year probability of survival from the start of IFN therapy probability of survival from the start of IFN therapy was 70 +/- 16% (95% CI) and was statistically higher for patients who achieved CCR than for the others.(ABSTRACT TRUNCATED AT 250 WORDS)

High response rate using recombinant interferon-alpha in patients with newly diagnosed chronic myeloid leukemia.

To improve the management of chronic myeloid leukemia (CML) in a single center, we have used interferon-alpha (IFN-alpha) to treat newly diagnosed Ph-positive CML patients and investigated the factors predictive of a major cytogenetic response. Eighty-one patients with a median age of 50.5 y (17-70) were given IFN-alpha (5 x 10(6)/sqm/day, s.c.). The median interval between diagnosis and IFN-alpha was 45 days (0-160). IFN-alpha doses were adjusted to maintain the white blood cell (WBC) count between 1.5 and 5 x 10(9)/l and the platelet count between 50 and 100 x 10(9)/l. At diagnosis, Sokal's criteria were used to classify patients into three groups: low (n = 39), intermediate (n = 32) and high risk (n = 10). A complete hematological response (CHR) was achieved in 66 cases (81.5%). Cytogenetic response was evaluated in these 66 responders. Thirty-six patients (44.4%) achieved a major cytogenetic response (MCR) (> or = 65% Ph-negative cells), 31 of them having a complete cytogenetic response. The 5-y transformation-free survival (TFS) of the 81 patients was 77 +/- 14% (95% CI) and was statistically influenced by the CHR rate at three months (p = 0.008) and the achievement of MCR or CCR (p < 0.0009 and p < 0.0005, respectively). Moreover, we found that the MCR or CCR were significantly influenced by the obtaining of CHR at three months (p < 0.001 and p < 0.0001, respectively). These results show that IFN-alpha can induce high rates of hematological and cytogenetic responses when administered in doses leading to myelosuppression. The achievement of CHR within three months could be useful to identify early those patients who will not respond to IFN-alpha and who need alternative treatments such as allogeneic or autologous stem cell transplantation.

Autologous stem cell transplantation in chronic myeloid leukemia: a single center experience.

Between 1980 and 1996, we transplanted 72 patients with CML using blood stem cells collected at diagnosis before treatment and without any mobilization. The median age of patients at diagnosis was 47.5 years (range 20.5-59.5). The median numbers of nucleated cells and CFU-GM transplanted were 10 x 10(8)/kg and 97 x 10(4)/kg, respectively. The median duration to reach more than 0.5 x 10(9)/l neutrophils and 50 x 10(9)/l platelets was 12 (range 5-19) and 11 days (range 0-79), respectively. Twenty patients (group I) were transplanted in chronic phase either for resistance to IFN (14 patients) (group IA) or because the Sokal index was more than 1.2 (six patients) (group IB). All those patients had preparative regimen with busulfan (4 mg/kg/day x 4) and melphalan (140 mg/m2). They were treated with recombinant alpha-interferon (IFN) after transplant. The cumulative incidence of major cytogenetic response (MCR) at 12 months was 25 +/- 21% (95% CI), the 5-year survival was 75 +/- 42% (95% CI). These results (observed in patients with bad prognosis factors) are similar to those usually observed in CML patients treated by IFN, whatever the Sokal risk. Thus autologous transplantation is able to reproduce for poor prognosis patients the results observed in standard risk patients treated with IFN. This suggests that it could prolong survival. Fifty-two other patients (group II) were transplanted for CML in transformation (accelerated phase = 32; blast crisis = 20) after a preparative regimen containing either total body irradiation (TBI) or busulfan. The median survival was short (10.4 months) and only 21 patients survived more than 1 year. The survival was longer for patients transplanted in accelerated phase (vs blast crisis), those who were due to receive a double transplant (vs single) (34 patients), those who were treated with IFN after transplant (vs hydroxyurea) and for the patients who obtained a complete hematologic response.

Factors influencing haemopoietic recovery following chemotherapy-mobilised autologous peripheral blood progenitor cell transplantation for haematological malignancies: a retrospective analysis of a 10-year single institution experience.

We retrospectively analysed the factors that influenced rate of haemopoietic recovery (HR) in 243 patients after transplantation with chemotherapy-mobilised autologous peripheral blood progenitor cells (PBPC). Approximately half the patients also received haemopoietic growth factors (HGF) for mobilisation. Conditioning for transplantation was with either chemotherapy alone or chemotherapy plus total body irradiation (TBI). Median time to recovery of granulocytes > or = 0.5 x 10(9)/l was 13 days (range 7-93 days) and of platelets > or = 50 x 10(9)/l 14 days (7-440). Speed of HR was greater, both for neutrophils and platelets for patients who received more rather than less CFU-GM than our median value of 18.9 x 10(4)/kg (P < 0.0001 in both instances) and more rather than less CD34-positive cells than our median value of 8.8 x 10(6)/kg (P < 0.0001 and P < 0.0005, respectively). For granulocyte recovery, in the multivariate analysis the dose of infused CFU-GM (P = 0.05) and the use of HGF for both mobilisation and post-transplantation (P < 0.0014) were significant positive factors. For platelet recovery in the multivariate analysis the dose of infused CFU-GM (P < 0.0016) was a positive factor. The use of busulphan and of TBI were significant adverse factors for rate of platelet recovery (P = 0.005 and 0.0004, respectively). When compared with non-HGF-mobilised PBPC, HGF-mobilised PBPC reduced the number of days of hospitalisation (28 vs 24, P = 0.0001) and of treatment with intravenous antibiotics (15 vs 11, P = 0.0004). These findings emphasise the importance of cell dose in accelerating haemopoietic recovery after autologous blood stem cell transplantation.