Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma.

We report follow-up results from the randomized, placebo-controlled, phase 3 HELIOS trial of ibrutinib+bendamustine and rituximab (BR) for previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without deletion 17p. Overall, 578 patients were randomized 1:1 to either ibrutinib (420 mg daily) or placebo, in combination with 6 cycles of BR, followed by ibrutinib or placebo alone. Median follow-up was 34.8 months (range: 0.1-45.8). Investigator-assessed median progression-free survival (PFS) was not reached for ibrutinib+BR, versus 14.3 months for placebo+BR (hazard ratio [HR] [95% CI], 0.206 [0.159-0.265]; P < 0.0001); 36-month PFS rates were 68.0% versus 13.9%, respectively. The results are consistent with the primary analysis findings (HR = 0.203, as assessed by independent review committee, with 17-month median follow-up). Median overall survival was not reached in either arm; HR (95% CI) for ibrutinib+BR versus placebo: 0.652 (0.454-0.935; P = 0.019). Minimal residual disease (MRD)-negative response rates were 26.3% for ibrutinib+BR and 6.2% for placebo+BR (P < 0.0001). Incidence of treatment-emergent adverse events (including grades 3-4) were generally consistent with the initial HELIOS report. These long-term data support improved survival outcomes and deepening responses with ibrutinib+BR compared with BR in relapsed CLL/SLL.

The CXCR4 inhibitor BL-8040 induces the apoptosis of AML blasts by downregulating ERK, BCL-2, MCL-1 and cyclin-D1 via altered miR-15a/16-1 expression.

CXCR4 is a key player in the retention and survival of human acute myeloid leukemia (AML) blasts in the bone marrow (BM) microenvironment. We studied the effects of the CXCR4 antagonist BL-8040 on the survival of AML blasts, and investigated the molecular mechanisms by which CXCR4 signaling inhibition leads to leukemic cell death. Treatment with BL-8040 induced the robust mobilization of AML blasts from the BM. In addition, AML cells exposed to BL-8040 underwent differentiation. Furthermore, BL-8040 induced the apoptosis of AML cells in vitro and in vivo. This apoptosis was mediated by the upregulation of miR-15a/miR-16-1, resulting in downregulation of the target genes BCL-2, MCL-1 and cyclin-D1. Overexpression of miR-15a/miR-16-1 directly induced leukemic cell death. BL-8040-induced apoptosis was also mediated by the inhibition of survival signals via the AKT/ERK pathways. Importantly, treatment with a BCL-2 inhibitor induced apoptosis and act together with BL-8040 to enhance cell death. BL-8040 also synergized with FLT3 inhibitors to induce AML cell death. Importantly, this combined treatment prolonged the survival of tumor-bearing mice and reduced minimal residual disease in vivo. Our results provide a rationale to test combination therapies employing BL-8040 and BCL-2 or FLT3 inhibitors to achieve increased efficacy of these agents.

Brentuximab vedotin in combination with or without donor lymphocyte infusion for patients with Hodgkin lymphoma after allogeneic stem cell transplantation.

In our study, we evaluated the safety and efficacy of Brentuximab vedotin (BV) with or without the addition of donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (allo-SCT) in 16 patients with advanced Hodgkin lymphoma (HL). Thirteen patients with relapsed HL after allo-SCT received BV as treatment for active disease. Three patients without progression of HL after allo-SCT received BV as consolidation. Twelve patients had been previously exposed to BV for treatment of relapse after autologous-SCT. Ten out of 16 patients received BV in combination with DLI. Among the 13 patients treated for active disease, CR and PR was observed in 7 and 2 patients, respectively. With a median follow-up of 13 months, 13 out of 16 patients are alive, while 3 died because of disease progression. The median PFS was 6 months. DLI-associated GVHD occurred in seven patients. Five patients with GVHD required immunosuppression, and in all cases, GVHD resolved after a short course of low dose steroids, implying that an anti-GVHD modulating effect could be induced by the concurrent administration of BV. No serious adverse event was observed in any of the patients.

Fludarabine and treosulfan compared with other reduced-intensity conditioning regimens for allogeneic stem cell transplantation in patients with lymphoid malignancies.

Allogeneic stem-cell transplantation (SCT) is a potentially curative therapy for lymphoid malignancies. Myeloablative conditioning is associated with high non-relapse mortality (NRM). Reduced-intensity condition (RIC) reduces NRM but relapse rate is increased. Novel regimens with intensive anti-malignancy activity but limited toxicity are of benefit. We evaluated outcomes of 144 lymphoma patients given allogeneic SCT with RIC consisting of fludarabine and treosulfan (FT, n=50), intravenous-busulfan (FB2, n=38) or melphalan (FM, n=56). Sixty-nine patients (48%) had chemo-sensitive disease and 75 (52%) had chemo-refractory disease at SCT. The median follow-up is 39 months (4-149). Three-year survival was 67, 74 and 48% after FT, FB2 and FM, in chemo-sensitive disease (P=0.14) and 34, 11 and 17% in chemo-refractory disease, respectively (P=0.08). Three-year NRM was 24, 24 and 54% (P=0.002), whereas relapse mortality was 22, 34 and 18%, respectively (P=0.13). Multivariate analysis identified a high comorbidity-score, chemo-refractory disease and FM as associated with shortened survival. In conclusion, FB2 is associated with low NRM and good results in chemo-sensitive disease, but with higher relapse mortality rates. FM controls disease better, but with high NRM. FT probably balances these outcomes more optimally. It is as safe as FB2 and as cytoreductive as FM, resulting in improved outcome, mostly in advanced disease.

Secondary malignancies after allogeneic stem-cell transplantation in the era of reduced-intensity conditioning; the incidence is not reduced.

Secondary malignancies are well established complication in long-term survivors after allogeneic stem-cell transplantation (SCT) with myeloablative conditioning (MAC). Fludarabine-based reduced-intensity (RIC) and reduced-toxicity conditioning (RTC) regimens are increasingly used in the last decade; however, due to limited long-term follow-up, there is no data on secondary malignancies in this setting. The records of 931 consecutive patients given allogeneic SCT with MAC (n=257), RIC (n=449) or RTC (n=225), in a single institution over a 13-year period, were reviewed. Twenty-seven patients had secondary malignancy, diagnosed a median of 43 months (7 months-11.5 years) after SCT. The 10-year cumulative incidence was 5.6% (95% confidence interval (CI), 3.6-8.7), twice the expected rate in matched normal population. The incidence was 1.7, 7.4 and 5.7% after MAC, RIC and RTC, respectively (P=0.02). Multivariate analysis identified fludarabine-based conditioning (hazard ratio (HR) 3.5, P=0.05), moderate-severe chronic graft-versus-host disease (HR 2.8, P=0.01) and diagnosis of chronic myeloproliferative or non-malignant disease (HR 0.2, P=0.04) as risk-factors for secondary malignancy. The related 10-year mortality rate was 2.4% (95% CI, 1.0-5.4). In conclusion, the risk of secondary malignancies is not reduced and is even possibly increased in the era of fludarabine-based RIC/RTC. Patients and physicians should be aware of this association and life-long cancer screening is required for all transplant survivors.

Two cycles of escalated BEACOPP followed by four cycles of ABVD utilizing early-interim PET/CT scan is an effective regimen for advanced high-risk Hodgkin's lymphoma.

BACKGROUND: Escalated combination therapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (escBEACOPP) regimen is superior to cyclophosphamide, vincristine, procarbazine and prednisone alternating with doxorubicin, bleomycin, vinblastine and dacarbazine (COPP-ABVD) for advanced-stage Hodgkin's lymphoma (HL) patients. However, the original schedule of eight cycles of escBEACOPP was associated with significant toxicity. This study was conducted in an attempt to reduce the toxicity of the original schedule, while attempting to preserve improved initial tumor control. PATIENTS AND METHODS: Forty-five newly diagnosed patients with advanced-stage HL and International Prognostic Score > or = 3 received two initial cycles of escBEACOPP and then were evaluated by positron emission tomography (PET)/computed tomography scan. If a good imaging response was obtained, they were treated by four cycles of ABVD. RESULTS: Following the first two cycles of escBEACOPP, the overall response was 100% and at the end of all therapy, 40 (89%) patients were in complete response (disappearance of all clinical evidence of disease and PET negativity), three (7%) in partial response (PET-positive residual lesions and a size reduction of the majority of large masses by >50%), while two (4%) had progressive disease. After a median follow-up of 48 months, progression-free survival (PFS) and overall survival at 4 years were 78% and 95%, respectively. The 4-year PFS for early PET-negative patients (n = 31) and early PET-positive patients (n = 13) were 87% and 53%, respectively (P = 0.01). CONCLUSIONS: These data indicate that combined escBEACOPP-ABVD may improve the outcome in patients with high-risk advanced HL. The potential benefit of early-interim PET activity as a guide to continuing therapy in these patients merits further study in the future.

Ibritumomab tiuxetan (Zevalin) combined with reduced-intensity conditioning and allogeneic stem-cell transplantation (SCT) in patients with chemorefractory non-Hodgkin's lymphoma.

Allogeneic SCT is an effective therapy for lymphoma. Reduced-intensity conditioning (RIC) reduces non-relapse mortality (NRM) associated with myeloablative conditioning but relapse rates are high when performed in active disease. This study was designed to explore the safety and outcome of ibritumomab tiuxetan (Zevalin) combined with RIC in patients with advanced lymphoma. The study included 12 patients, median age 54 years (37-62), with a median of four prior treatments (2-6) and active disease documented on PET-CT. Zevalin 0.4 mCi/kg was given on day -14 and fludarabine combined with BU (n=6) or melphalan (n=6) was started on day -6. GVHD prevention was tapered 3 months after SCT to augment the graft-versus-lymphoma effect. All patients engrafted, a median of 14 days after SCT. Eighty-three percent achieved CR/PR. With a median follow-up of 21 months (12-37), 2-year PFS is 33%. Only three patients relapsed; cumulative incidence 25%. NRM was 42%, predominantly due to acute GVHD. Zevalin-RIC is feasible with consistent engraftment, acceptable organ toxicity, but high rates of acute GVHD. The low incidence of relapse suggests augmented anti-lymphoma effect. Zevalin-RIC merits further study. Better results may be achieved in patients earlier in disease course and with longer duration of immune-suppression.

Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells.

Tumors contain a fraction of cancer stem cells that maintain the propagation of the disease. The CD34(+)CD38(-) cells, isolated from acute myeloid leukemia (AML), were shown to be enriched leukemic stem cells (LSC). We isolated the CD34(+)CD38(-) cell fraction from AML and compared their gene expression profiles to the CD34(+)CD38(+) cell fraction, using microarrays. We found 409 genes that were at least twofold over- or underexpressed between the two cell populations. These include underexpression of DNA repair, signal transduction and cell cycle genes, consistent with the relative quiescence of stem cells, and chromosomal aberrations and mutations of leukemic cells. Comparison of the LSC expression data to that of normal hematopoietic stem cells (HSC) revealed that 34% of the modulated genes are shared by both LSC and HSC, supporting the suggestion that the LSC originated within the HSC progenitors. We focused on the Notch pathway since Jagged-2, a Notch ligand was found to be overexpressed in the LSC samples. We show that DAPT, an inhibitor of gamma-secretase, a protease that is involved in Jagged and Notch signaling, inhibits LSC growth in colony formation assays. Identification of additional genes that regulate LSC self-renewal may provide new targets for therapy.

Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity.

Allogeneic stem-cell transplantation (SCT) with both myeloablative and reduced-intensity conditioning (RIC) is an effective therapy in AML/MDS. However, the relative merits of each may differ in different settings. To define the role of dose intensity, we analyzed SCT outcomes of 112 consecutive patients with AML/MDS. A total of 45 patients met eligibility criteria for standard myeloablative conditioning and were given intravenous-busulfan (12.8 mg/kg) and cyclophosphamide (ivBuCy). A total of 67 noneligible patients were given RIC with fludarabine and intravenous-busulfan (6.4 mg/kg, FB2, n=41) or a modified myeloablative regimen with fludarabine and myeloablative doses of intravenous-busulfan (12.8 mg/kg, FB4, n=26). The overall survival (OS) at 2 years was 50, 49 and 47% after ivBuCy, FB4 and FB2, respectively (P=NS). Nonrelapse mortality was higher after ivBuCy, 22 vs 8% (P=0.05), but relapse rates were lower. Active disease at SCT was the most significant predictor of reduced survival in multivariable analysis (HR 4.5, P=0.0001). Myeloablative and RIC regimens had similar outcomes when leukemia was in remission at SCT; however, patients with active disease could only be salvaged by myeloablative conditioning. Among the latter, OS was 45% after ivBuCy but no FB2 recipient survived (P=0.02). Patients with active disease, ineligible for standard myeloablation, could tolerate modified myeloablation well; however, long-term outcome cannot be determined yet.

Hematopoietic stem-cell transplantation from unrelated donors in elderly patients (age >55 years) with hematologic malignancies: older age is no longer a contraindication when using reduced intensity conditioning.

Allogeneic stem cell transplantation (SCT) is a potentially curative approach for patients with hematological malignancies. Reduced-intensity conditioning regimens allow SCT in elderly patients; however, there are only limited data on the feasibility and outcomes of unrelated donor SCT in these patients. In this study, we analyzed, retrospectively, data of 36 patients with various hematological malignancies and median age 58 years (range, 55-66), who were given unrelated donor SCT after reduced-intensity conditioning. The preparative regimen consisted of fludarabine combined with oral busulfan (8 mg/kg, n=8), intravenous busulfan (6.4 mg/kg, n=11), treosulfan (30 g/m(2), n=5) or melphalan (100-150 mg/m(2), n=12). Patients were also given serotherapy, ATG (n=32), or alemtuzumab (n=4). The probabilities of overall survival, disease-free survival, and nonrelapse mortality at 1 year after SCT were 52, 43, and 39%, respectively. Acute graft-versus-host disease (GVHD) grade II-IV and chronic GVHD occurred in 31 and 45%, respectively. Multivariable analysis determined that survival rates were higher in patients with chemosensitive disease (HR 4.5), and patients conditioned with intravenous busulfan or treosulfan (HR 3.9). Unrelated donor SCT is feasible in elderly patients, with outcomes that are similar to younger patients. Favorable outcome was observed in patients with myeloid malignancies, and those transplanted in remission and early in the course of disease. Age alone should not be considered a contraindication to unrelated donor SCT.

Outcome and prognostic factors in advanced Hodgkin's disease treated with high-dose chemotherapy and autologous stem cell transplantation: a study of 341 patients.

BACKGROUND: The reported probability of survival of patients with Hodgkin's disease (HD) following high-dose chemotherapy with autologous stem cell transplantation (HDC/ASCT) is 35-65% at 5 years. The Polish Lymphoma Research Group investigated retrospectively prognostic factors for overall survival (OS) and event-free survival (EFS), and the risk of secondary malignancies in a large series of patients who underwent HDC/ASCT. PATIENTS AND METHODS: The data of 341 consecutive patients treated in 10 centers from 1990 to 2002 were collected and analyzed. RESULTS: The actuarial 5-year OS and EFS were 64% [95% confidence interval (CI) 57% to 71%] and 45% (95% CI 39% to 51%), respectively. In the multivariate model, unfavorable prognostic factors for EFS were less than partial response at the time of ASCT [relative risk (RR), 2.92 (95% CI 1.68-5.08); P<0.001] and three or more previous chemotherapy lines (RR, 2.16; 95% CI 1.42-3.30; P<0.001). These two factors were also associated with unfavorable OS (RR, 3.32; 95% CI 1.90-5.79; P<0.001 and RR, 2.34, 95% CI 1.51-3.64; P<0.001). Five-year cumulative risk of secondary malignancy was 8.4% (95% CI 2% to 13%) and the only identified risk factor was splenectomy (P=0.02). CONCLUSIONS: HDC/ASCT should be considered early in the course of disease for patients with a response after standard therapy.

Treatment for primary refractory Hodgkin's disease: a comparison of high-dose chemotherapy followed by ASCT with conventional therapy.

Our previously published study showed promising results of autologous stem cell transplantation (ASCT) in patients with primary resistant Hodgkin's disease (HD). Probabilities of overall survival (OS) and progression-free survival (PFS) at 3 years were 55 and 36%, respectively. The present study was undertaken to compare these results with conventionally treated patients and thus evaluate therapeutic options. Retrospective data on 76 adult patients who underwent ASCT were matched with 76 conventionally treated patients from 17 centers. Comparison of clinical characteristics in both groups showed that ASCT patients were younger (24 vs 31.5 years, P=0.001), more frequently presented with 'B' symptoms (P=0.03) and that more patients treated with chemotherapy (CT) had elevated LDH (P=0.03). In univariate analyses, bulky disease (P=0.0043) and complete resistance to standard CT (P=0.051) were found to be risk factors for OS. In a multivariate survival analysis only bulky disease was found to an independent prognostic factor (P=0.005). There was no difference in survival between the treatment groups with 5 years OS 33.7 (CI: 23-46) in the ASCT group and 35.6% (CI: 25-50) for the CT group (P=0.92). We conclude that ASCT is not superior to standard CT for treatment of patients with primary refractory HD.

Imatinib mesylate (STI571) in preparation for allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusions in patients with Philadelphia-positive acute leukemias.

Chronic myeloid leukemia in blast crisis (BC) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) are associated with extremely poor outcome. Allogeneic transplantation during BC or active leukemia is most often unsuccessful due to high-rates of both treatment-related complications and relapse. Long-term results are significantly better if a second chronic phase or remission can be achieved prior to transplantation. Similarly, DLI given for the treatment of post-transplant relapse is more successful when given during a second remission. In this study we report our results with a previously unreported approach consisting of short-term treatment with imatinib mesylate (formerly, STI571) to induce or maintain remission, followed by allogeneic transplantation or DLI and the impact on transplantation/DLI outcome. Sixteen patients were treated either in preparation for transplantation (n = 12), for DLI (n = 1), or for both (n = 3). Ten had CML in BC; seven myeloid and three lymphoid BC. Six patients had Ph(+) ALL. The donors were matched unrelated (n = 9), matched siblings (n = 5) or haplo-identical (n = 2). Eleven of 15 patients given imatinib pre-transplant were transplanted in complete hematologic response. Engraftment and GVHD rates were not different from expected. Seven patients had grade II-III hepatic toxicity after transplantation. After a median follow-up of 10 months (range, 3-16 months) six remain alive, two after further therapy. The 1-year survival rate was 25%. Four patients were given imatinib prior to DLI, all had complete response. Two remain in remission >6 months from relapse. In conclusion, treatment with imatinib allows transplantation in a more favorable status or maintaining remission with low toxicity until transplantation is feasible. Pre-transplant imatinib seems safe and not associated with excess post-transplant complications. Imatinib may have substantial activity in combination with DLI. Further study of a larger group of patients is required to assess the impact on long-term outcome and the role of post-transplant imatinib in controlling residual disease.

Chimerism testing and detection of minimal residual disease after allogeneic hematopoietic transplantation using the bioView (Duet) combined morphological and cytogenetical analysis.

Recurrent disease remains a major obstacle to cure after allogeneic transplantation. Various methods have been developed to detect minimal residual disease (MRD) after transplantation to identify patients at risk for relapse. Chimerism tests differentiate recipient and donor cells and are used to identify MRD when there are no other disease-specific markers. The detection of MRD does not always correlate with relapse risk. Chimerism testing may also identify normal hematopoietic cells or other cells not contributing to relapse. In this study we report our initial experience with a novel system that provides combined morphological and cytogenetical analysis on the same cells. This system allows rapid automatic scanning of a large number of cells, thus increasing the sensitivity of detection of small recipient population. The clinical significance of MRD detection is improved by identifying the morphology of recipient cells. Identification of recipient characteristics within blasts predicts overt relapse in leukemia patients and precedes it by a few weeks to months. Identification within mature hematopoietic cells may not be closely associated with relapse. The system also allows chimerism testing after sex-mismatched transplants, within cellular subsets, with no need for sorting of cells. The system merits further study in larger scale trials.

Extramedullary progression despite a good response in the bone marrow in patients treated with thalidomide for multiple myeloma.

We report two patients who were treated with thalidomide for resistant multiple myeloma (MM) and developed extramedullary plasmacytomas despite a good response in the bone marrow. The first patient had progressive disease 18 months post autologous peripheral stem cell transplant. Two and a half months after the initiation of thalidomide therapy extensive new plasmacytomas of the skin and nasal mucosa appeared while the medullary response continued. The second patient was treated with thalidomide for resistant MM. Despite a medullary response he developed neurological signs compatible with cranial nerve involvement and an MRI study was suggestive of a plasmacytoma involving the sellar region. We assume that a change in the expression of some adhesion molecules on the myeloma and/or the stromal cells is responsible for this phenomenon. Treating Physicians should be aware of this phenomenon in MM patients receiving thalidomide.

Engraftment-associated hypophosphatemia--the role of cytokine release and steep leukocyte rise post stem cell transplantation.

Hypophosphatemia associated with bone marrow transplantation has been infrequently reported. The suggested mechanism is phosphate uptake by the replicating cells. Various cytokines are associated with the development of hypophosphatemia. The present study evaluated the interrelationship between cytokine release, the rise in WBC and the development of hypophosphatemia during the engraftment period. Blood samples were obtained from 60 patients undergoing peripheral blood stem cell transplant, on the day of admission and then daily from the day of transplant until discharge. Hypophosphatemia developed in 62% of the patients. The median day of minimal phosphorus level was +8 and it antedated engraftment by 2 days. There was a significant correlation between the day of minimal phosphorus level and the day of maximal WBC and a significant correlation between the fall in phosphorus level and WBC rise. IL-6 and IL-8 showed similar kinetics. Higher IL-6 and IL-8 levels were directly associated with lower phosphorus levels. In conclusion, hypophosphatemia commonly occurs in the post-transplant period. We assume that both a direct effect of cytokine release and an increased consumption by the dividing WBCs contribute to its appearance. As its occurrence usually antedates engraftment it can be used as a forerunner for WBC recovery.

[High-dose chemotherapy and autologous stem cell transplantation for refractory and relapsing Hodgkin's disease as first-line therapy-- studies at Sheba Medical Center--Tel Hashomer].

High dose chemotherapy and autologous stem cell transplantation are widely used in relapsed and primary refractory Hodgkin's disease. We transplanted 42 patients with Hodgkin's disease between 1990-1998. Median follow-up was 31 months (range 1-102). 29 (69%) were transplanted after relapse and 13 (31%) were refractory to first line therapy. Median age at transplantation was 29 years (range 19-58) and 23 (55%) were males. All were treated with the BEAM protocol (carmustine, etoposide, cytarabine and melphelan). 18 who were in remission received radiotherapy following transplantation. The source of the stem cells was bone marrow in 17% and peripheral blood in 83%. At initial diagnosis: 57% had stage III-IV disease and B symptoms were present in 52%. 75% were treated with MOPP, ABVD or with related versions. Radiotherapy followed in 52%. Prior to transplantation, 45% of the relapsed group were in the advanced stage. 33% and 12% of all patients had lung and bone involvement, respectively. The complete remission rate was 86% for the 2 groups. 2 (5%) died from transplant-related complications and MDS/AML developed in 2 (5%) after transplantation. The 3-year overall survival (OS) and disease-free survival (DFS) were 68% and 60%, respectively. The 3-year OS for the relapsed group was 64% compared with 76% for the refractory group, and the 3-year DFS for the relapsed group was 60% vs. 42% for the refractory group (neither difference significant). Radiotherapy following transplantation did not have a beneficial effect on DFS. No prognostic factors for outcome of transplantation were found, most probably due to the limited number of patients and the high variability of disease characteristics. We conclude that high dose chemotherapy and autologous stem cell transplantation are effective and relatively safe for relapsed or primary refractory Hodgkin's disease. The DFS at 3 years was longer for those transplanted after relapse than those with primary refractory disease, but not significantly. Patients with primary refractory disease can be salvaged with high dose chemotherapy.

Diffuse alveolar hemorrhage in acute promyelocytic leukemia patients treated with ATRA--a manifestation of the basic disease or the treatment.

All-trans-retinoic acid (ATRA) is considered the recommended induction treatment for acute promyelocytic leukemia. In the pre-ATRA era pulmonary bleeding was a common cause of death in these patients, mostly due to disseminated intravascular coagulation which was further exacerbated by the administration of chemotherapy. Although ATRA syndrome, the most serious adverse effect of ATRA treatment, involves the lungs, pulmonary hemorrhage has only rarely been reported as a manifestation of ATRA syndrome. Here we describe 2 patients who developed diffuse alveolar hemorrhage during treatment with ATRA. The possible mechanisms of pulmonary bleeding in these cases are discussed.

Therapy with thalidomide in refractory multiple myeloma patients - the revival of an old drug.

We have treated 17 refractory or relapsed multiple myeloma patients resistant to chemotherapy with thalidomide at a dose of 200-800 mg/day. Eleven patients responded, five of whom had a very good partial response (> 75% decline in M protein) and another five exhibited a partial response (> 50% decline in M protein). Except for one patient, treatment was well tolerated with only mild side-effects. Thalidomide should be included in the therapeutic options for refractory myeloma.

Salvage therapy of refractory and relapsed acute leukemia with high dose mitoxantrone and high dose cytarabine.

We have assessed the outcome of 66 refractory and relapsed acute leukemia patients treated with high dose mitoxantrone and cytarabine. Therapy consisted of a total dose of 40-60 mg/m2 mitoxantrone and 3 g/m2 of cytarabine daily on 5 consecutive days. A total of 28 patients were treated for primary resistant and 38 patients for early or late relapsed leukemia. A total of 35 patients achieved CR. Four patients died during the induction course. Toxicity was acceptable and comparable to other salvage regimens. The median disease-free and overall survivals were 4 and 6 months, respectively. Although this regimen is effective in achieving remission in refractory leukemia, its duration is short.