Treatment discontinuation following low-dose TKIs in 248 chronic myeloid leukemia patients: Updated results from a campus CML real-life study.

TKIs long-term treatment in CML may lead to persistent adverse events (AEs) that can promote relevant morbidity and mortality. Consequently, TKIs dose reduction is often used to prevent AEs. However, data on its impact on successful treatment-free remission (TFR) are quite scarce. We conducted a retrospective study on the outcome of CML subjects who discontinued low-dose TKIs from 54 Italian hematology centers participating in the Campus CML network. Overall, 1.785 of 5.108 (35.0%) regularly followed CML patients were treated with low-dose TKIs, more frequently due to relevant comorbidities or AEs (1.288, 72.2%). TFR was attempted in 248 (13.9%) subjects, all but three while in deep molecular response (DMR). After a median follow-up of 24.9 months, 172 (69.4%) patients were still in TFR. TFR outcome was not influenced by gender, Sokal/ELTS risk scores, prior interferon, number and last type of TKI used prior to treatment cessation, DMR degree, reason for dose reduction or median TKIs duration. Conversely, TFR probability was significantly better in the absence of resistance to any prior TKI. In addition, patients with a longer DMR duration before TKI discontinuation (i.e., >6.8 years) and those with an e14a2 BCR::ABL1 transcript type showed a trend towards prolonged TFR. It should also be emphasized that only 30.6% of our cases suffered from molecular relapse, less than reported during full-dose TKI treatment. The use of low-dose TKIs does not appear to affect the likelihood of achieving a DMR and thus trying a treatment withdrawal, but might even promote the TFR rate.

Concomitant and sequential administration of recombinant human granulocyte colony-stimulating factor and recombinant human interleukin-3 to accelerate hematopoietic recovery after autologous bone marrow transplantation for malignant lymphoma.

PURPOSE: To assess the safety, tolerability, and hematopoietic efficacy of sequential and concomitant administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human interleukin-3 (rhIL-3), to accelerate reconstitution of hematopoiesis following myeloablative chemotherapy and autologous bone marrow transplantation (ABMT) for heavily pretreated lymphoma patients. PATIENTS AND METHODS: Fifty-four consecutive patients with refractory or relapsed non-Hodgkin's lymphoma (NHL; n = 30) and Hodgkin's disease (HD; n = 24) were studied. Two different conditioning regimens were used for ABMT: carmustine, cyclophosphamide, etoposide, and cytarabine (BAVC) and carmustine, melphalan, etoposide, and cytarabine (BEAM) for NHL and HD, respectively. Patients were enrolled sequentially onto one of three treatment groups: group 1, G-CSF (5 micrograms/kg/d subcutaneously [SC]) from day +1 after reinfusion of autologous marrow (n = 23); group 2, G-CSF from day +1 combined with IL-3 (10 micrograms/kg/d SC) from day +6 (n = 22, overlapping schedule); and group 3, G-CSF treatment discontinued at day +6 before initiation of IL-3 administration (n = 9, sequential schedule). In the three groups, growth factor(s) was administered until the granulocyte count was greater than 0.5 x 10(9)/L for 3 consecutive days. RESULTS: The study cytokines were generally well tolerated. No side effects were observed when G-CSF was given alone. Four of 31 patients (12.9%) who received SC IL-3 had one severe adverse event defined as World Health Organization (WHO) grade 3 to 4 toxicity (fever, n = 2; pulmonary toxicity, n = 2) and were withdrawn from the study. Groups 2 and 3 did not differ as for treatment tolerability, whereas we observed a trend toward a faster hematopoietic recovery when IL-3 was administered concomitant with G-CSF from day 6 (ie, group 2). Pooled together, patients who received IL-3 showed a median time to achieve a granulocyte count greater than 0.1 and greater than 0.5 x 10(9)/L of 8 and 11 days, respectively. The median time to an unsupported platelet count greater than 20 and 50 x 10(9)/L was 15 and 20 days, respectively, and only one patient did not reach a normal platelet count. The median number of days to hospital discharge was 16 after ABMT (range, 12 to 29). When the hematologic reconstitution of patients in groups 2 and 3 was compared with that of patients in group 1, the addition of IL-3 resulted in a significant improvement of multilineage hematopoietic recovery, lower transfusion requirements, a lower number of documented infections, and shorter hospitalizations. CONCLUSION: We conclude that the combination of G-CSF and IL-3 is safe and well tolerated in intensively pretreated lymphoma patients, undergoing ABMT and results in rapid hematopoietic recovery following myeloablative chemotherapy.

Autologous bone marrow transplantation in late first complete remission improves outcome in acute myelogenous leukemia.

We evaluated the role of ABMT in late 1st CR AML adult patients using busulfan plus cyclophosphamide as preparative regimen. Fifty-one adult patients (mean age 36 years, range 15-59) with AML underwent ABMT in 1st CR. Three of them had a prior diagnosis of myelodysplastic syndrome; one patient had a secondary leukemia. The median interval between CR and ABMT was 8 months (range 4-20). Patients received busulfan, 4 mg/kg/day for 4 days plus cyclophosphamide 50 mg/kg/day for 4 days or 60 mg/kg/day for 2 days. No maintenance chemotherapy was administered after ABMT. Median days to reach 0.5 x 10(9)/I PMN and 20 x 10(9)/I platelets were 26 (range 12-250) and 74 (range 16-740), respectively. No transplant-related deaths were observed. Five-year actuarial overall survival rate is 76.9%; actuarial leukemia-free survival rate is 70.6%. Mean follow-up from ABMT is 35 months. Leukemia-free survival of this group was compared with that of 38 non-transplanted patients younger than 60 years, who maintained a CR longer than 8 months in the same period. This analysis shows a statistically significant difference in favor of ABMT patients. These results suggest that, even if performed late after 1st CR as post-remission intensification, ABMT can improve the outcome of AML patients.

Proliferative response of human marrow myeloid progenitor cells to in vivo treatment with granulocyte colony-stimulating factor alone and in combination with interleukin-3 after autologous bone marrow transplantation.

We have recently reported that the hematologic recovery of patients with non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) undergoing autologous bone marrow transplantation (BMT) is significantly faster when recombinant human interleukin-3 (rhIL-3) is combined with recombinant human granulocyte colony-stimulating factor (rhG-CSF) in comparison with patients receiving G-CSF alone. In this paper, we studied the kinetic response and concentration of BM progenitor cells of 17 patients with lymphoid malignancies submitted to autologous BMT and treated with the G-CSF/IL-3 combination. The results were compared with those of five lymphoma patients receiving the same pretransplant conditioning regimen followed by G-CSF alone. rhG-CSF was administered as a single subcutaneous (sc) injection at the dose of 5 micrograms/kg/d from day 1 after reinfusion of autologous stem cells; rhIL-3 was added from day 6 at the dose of 10 micrograms/kg/d sc (overlapping schedule). In both groups (G-CSF- and G-CSF/IL-3-treated patients), cytokine administration was discontinued when the absolute neutrophil count (ANC) was >0.5 x 10(9)/L of peripheral blood (PB) for 3 consecutive days. After treatment with the CSF combination, the percentage of marrow colony-forming units-granulocyte/macrophage (CFU-GM) and erythroid progenitors (BFU-E) in S phase of the cell cycle increased from 9.3 +/- 2% to 33.3 +/- 12% and from 14.6 +/- 3% to 35 +/- 6%, respectively (p < 0.05). Similarly, we observed an increased number of actively cycling megakaryocyte progenitors (CFU-MK and BFU-MK). Conversely, G-CSF augmented the proliferative rate of CFU-GM (22.6 +/- 0.6% compared to a baseline value of 11.5 +/- 3%; p < 0.05) but not of BFU-E, CFU-MK, or BFU-MK, and the increase of S-phase CFU-GM was significantly lower than that observed in the posttreatment samples of patients receiving IL-3 in addition to G-CSF. The frequency of hematopoietic precursors in the BM, expressed as the number of colonies formed per number of cells plated, was unchanged or slightly decreased in both groups of patients. Because of the increase in marrow cellularity, however, a significant augmentation of the absolute number of both CFU-GM (3605 +/- 712/mL BM vs. 2213 +/- 580/mL; p < 0.05) and BFU-E (4373 +/- 608/mL vs. 3027 +/- 516/mL; p < 0.05) was reported after treatment with G-CSF/IL-3 but not G-CSF alone. Similarly, administration of the cytokine combination resulted in a higher number of CD34+ cells/mL BM, and their concentration was significantly greater than that observed in the posttreatment samples of G-CSF patients. Finally, we investigated the responsiveness to CSFs, in vitro, of highly enriched CD34+ cells, collected after priming with G-CSF in vivo (i.e., after 5 days of G-CSF administration). Our results demonstrated that pretreatment with G-CSF modified the response of BM cells to subsequent stimulation with additional CSFs. The results presented in this paper indicate that in vivo administration of two cytokines increases the proliferative rate and concentration of BM progenitor cells to a greater degree than G-CSF alone. These results support the role of growth factor combinations for accelerating hematopoietic recovery after high-dose chemotherapy.

Cytogenetic events after bone marrow transplantation for Philadelphia chromosome positive chronic myeloid leukemia.

Allogeneic bone marrow transplantation is the only way to cure patients with Ph1+ chronic myeloid leukemia. It is commonly assumed that, in order to obtain a cure for the patients, the leukemic clone must be completely destroyed by the conditioning treatment and the donor's bone marrow must repopulate the hemopoietic niches leading to a "complete chimera". However, cytogenetic analyses, supported by molecular ones, indicate that Ph1+ cells, far from being completely destroyed by chemo-radiotherapy may persist for a long time, probably in the majority of the patients. As demonstrated by the outcome of patients receiving T-cell depleted marrow, immune mechanisms must be involved in controlling and progressively reducing the size of the residual leukemic clone. Furthermore, immunodulating therapeutic strategies, represented by cyclosporin-A discontinuation or alpha interferon treatment, may successfully reduce the Ph1+ cell population even after a full relapse.

Hypercoagulability in patients undergoing autologous or allogeneic BMT for hematological malignancies.

Severe thrombotic alterations, such as veno-occlusive disease of the liver, may occur in the early phase following high-dose chemoradiotherapy and BMT. In this study, performed in patients with hematological malignancies subjected to allogeneic (10 cases) and autologous (20 cases) BMT, we have monitored laboratory hemostatic parameters to better understand the pathogenetic mechanism of thrombosis and particularly of veno-occlusive disease. Prothrombin time, activated partial thromboplastin time, plasma fibrinogen, markers of hypercoagulability (thrombin-antithrombin complex and prothrombin fragment F1+2); natural anticoagulants (protein C, protein S and antithrombin) together with fibrinolytic parameters (plasminogen, alpha 2-antiplasmin, tissue-plasminogen activator, plasminogen activator inhibitor and D-dimer) were assessed before transplant, on day 0 and weekly for 1 month thereafter. A hypercoagulability state, not related to an impairment of the anticoagulant and fibrinolytic systems, was documented before and after autologous and allogeneic transplant. Two patients developed veno-occlusive disease: they did not show any difference from the other patients before transplant while they presented a decrease of the natural anticoagulants along with altered fibrinolytic parameters only at the clinical onset of veno-occlusive disease. In conclusion, in this study a state of marked hypercoagulability was documented in BMT patients and the hemostatic laboratory parameters evaluated were not able to predict the occurrence of the thrombotic complications.

Immunologic and clinical modifications following low-dose subcutaneous administration of rIL-2 in non-Hodgkin's lymphoma patients after autologous bone marrow transplantation.

In order to induce a therapeutic immunomodulatory activity, 11 patients with high-grade non-Hodgkin's lymphoma (HG-NHL) at a median of 42 days after autologous bone marrow transplantation (ABMT) received recombinant interleukin-2 (rIL-2) subcutaneously at a dose of 2 international megaunits (IMU)/m2 every other day for 2 weeks and then 3 IMU/m2 twice a week for 1 year. Immunological studies, including T and natural killer (NK) cell subset assessment, together with functional assay, such as NK and CD16-mediated cytotoxic activities, were performed before therapy, after 2 weeks and then monthly. Phenotypic analyses showed a significant and persistant (P = 0.001) increase in the proportion and absolute number of total lymphocytes and, particularly of both CD16 and CD56 NK cells, from pre-treatment values of 14 and 18% to 30 and 38% respectively, recorded after 6 months of therapy. No changes were observed in CD25 (p55)-positive cells, while a significant increase from 13 to 33% (after 6 months) was observed in CD122-positive cells. Furthermore, rIL-2 administration led to an enhancement of NK activity even at the lowest effector:target ratio and of CD16-mediated cytotoxic activity. Clinical tolerance was acceptable with moderate fever and fluid retention observed only at the onset of rIL-2 treatment. None of the patients have progressed with a median follow-up of 22 months (range 10-42 months) after starting therapy. In addition, two patients with a residual disease after ABMT, one in the liver and the second in the lymph nodes, obtained a complete response after 10 and 7 months of rIL-2 therapy, respectively. These preliminary data suggest that the infusion of low-dose rIL-2 s.c. after ABMT is safe and well tolerated and can selectively increase the NK cell number and function. Additional patients are needed in order to assess the impact of these immunological changes on relapse-free survival after ABMT for HG-NHL.

Detection of occasional and clonal chromosome aberrations in patients with acute non-lymphocytic leukemia after autologous bone marrow transplantation.

Clonal chromosome aberrations observed in patients who have relapsed after autologous bone marrow transplantation (ABMT) are usually related to the cytogenetic abnormalities observed at diagnosis. In order to assess this relationship, we evaluated 30 acute non-lymphocytic leukemia (ANLL) patients who underwent ABMT at out institution and had evaluable serial cytogenetic studies before and after ABMT. Seventeen patients (57%) showed no chromosome aberrations after ABMT in any of the studies performed, while 13 patients (43%) carried abnormalities. In eight out of 30 patients (27%0 the abnormal karyotype after ABMT was associated with hematologic relapse. The cytogenetic abnormalities were: (1) the same as at diagnosis without additional abnormalities in five patients; (2) the same as at diagnosis but with additional abnormalities in three patients. In one patient a different karyotype from that of diagnosis was detected and a myelodysplastic syndrome was clinically evaluable. Furthermore, occasional and single cell chromosome abnormalities were observed in four patients (13%), none of whom relapsed. The new and additional clonal cytogenetic abnormalities observed after ABMT were found in eight patients (27%), suggesting that this event may not be so frequent, that is presumably associated regimen. The re-appearance of the chromosome aberrations after ABMT and the relationship with the risk of relapse are discussed.

Allogeneic bone marrow transplantation for multiple myeloma.

Seventeen patients received marrow transplants from their HLA-matched, MLC-negative, sibling donors. Nine patients had progressive disease not responding to conventional treatments, while the other 8 patients were rated as responders. The most frequently used conditioning regimen consisted of total body irradiation and high-dose multi-agent chemotherapy with cyclophosphamide plus either oral melphalan (5 cases) or BCNU (1 case) on both these drugs (7 cases). Twelve patients were valuable for response to BTM: 7 of them (6 responders and 1 with advanced refractory MM) entered complete remission, while 5 had sustained decrease in tumor mass that ranged between 72% and 93%. Eleven patients died of transplant-related causes, 1 of them with signs of progressive disease. The remaining 6 patients are alive and 5 of them maintain a complete remission status 4 to 67 (median 36) months after BMT.

An unusual case of Candida tropicalis sepsis in a patient submitted to allogeneic bone marrow transplantation.

We describe an exceptional case of Candida tropicalis sepsis in a patient submitted to allogeneic BMT; the diagnosis was made on a peripheral blood smear, when the pt was neutropenic and only mildly febrile. The combination of GM-CSF to accelerate hematological recovery and the possibility of administering large doses of a liposomal form of Amphotericin B were the contributing factors to the resolution of the infection.

Low doses of rIL2 after autologous bone marrow transplantation induce a "prolonged" immunostimulation of NK compartment in high-grade non-Hodgkin's lymphomas.

Ten patients with high-grade non-Hodgkin's lymphoma (HG-NHL) entered a subcutaneous (s.c.) recombinant interleukin 2 (rIL2) trial within 2 months of undergoing autologous bone marrow transplantation (ABMT). Immunological studies, consisting in T- and natural killer (NK)-cell subset assessment, together with functional assays, such as NK activity and CD16-mediated redirected killing assay, were performed before therapy, after 2 weeks, and then monthly. Phenotypic analysis showed a significant increase (p = 0.01) of CD16 and CD56 NK cells, from 12% to 28% and from 17% to 37%, respectively. In particular, the CD56bright NK cell population showed a tenfold increase, while CD56dim NK cells remained unmodified compared with pretreatment values. The expression of IL2 receptors was also studied and a significant increase (p = 0.01) of CD122 (p75)-positive cells from 8% to 30% was found, while no significant increase was observed in CD25 (p55)-positive cells. Furthermore, rIL2 administration led to an increase of NK activity even at the lowest effectors:target ratio and to an increase of CD16-mediated redirected killing assay. These phenotypic and functional modifications lasted throughout the duration of rIL2 therapy and remained after completion of therapy. In addition, none of the ten patients relapsed, and two of them who started IL2 treatment while still showing residual disease experienced a complete disappearance of the disease after 10 and 7 months of therapy, respectively. Our data suggest that infusion of rIL2 s.c. after ABMT is safe, can selectively increase NK cell number and function, and may have a beneficial effect on the minimal residual disease.

VNCOP-B regimen in the treatment of high-grade non-Hodgkin's lymphoma in the elderly.

BACKGROUND: Age is an important factor, especially in patients with advanced lymphoma who require more intensive and extensive therapy for any possible chance of cure. In fact, attenuation of treatment to diminish treatment-related toxicity decreases the capacity of the therapy to effect a cure. METHODS: Between December, 1991 and February 1993, 29 previously untreated patients 60 years and older with high-grade non-Hodgkin's lymphoma (HG-NHL), according to the Kiel classification, were treated with a combination therapy including cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin, and prednisone (VNCOP-B). RESULTS: Twenty-two patients achieved a complete pathologic remission and 5 had a partial response, with a reduction of more than 50% of tumor-related manifestations. Only two cases were resistant to VNCOP-B. Overall survival was 75%, with a median follow-up of 13 months from diagnosis; four of the patients who achieved complete response relapsed after a median follow-up of 11 months from the completion of treatment. Clinical and hematologic toxicity was irrelevant: in 12 patients, neutropenia was responsible for a temporary interruption of therapy for 1-2 weeks. CONCLUSIONS: This regimen was effective in inducing a good remission rate with moderate toxic effects in elderly patients with HG-NHL, but a longer follow-up is warranted before definitive conclusions can be drawn.

Hematological recovery after autologous bone marrow transplantation for high-grade non Hodgkin's lymphomas: a single center experience.

BACKGROUND: Both rhGM-CSF and rhG-CSF can accelerate hematological recovery after high-dose therapy and autologous bone marrow transplantation in patients with high grade non Hodgkin's lymphoma and reduce transplant-related morbidity after ABMT. METHODS: The clinical course of 23 non randomized patients was analyzed and compared with a historical control group of 10 patients. Ten patients received GM-CSF at a dose of 10 micrograms/kg in a 6-h IV infusion, and 13 received G-CSF at a dose of 5 micrograms/kg subcutaneously. Control patients received no GFs. RESULTS: Mean granulocytic recovery to 0.5 x 10(9)/L was obtained 13.1 +/- 3.2 days after marrow reinfusion in the G-CSF arm vs 16 +/- 2.7 in GM-CSF pts (p = 0.03) and vs 19.6 +/- 7.6 in controls (p < 0.01); this reduction led to a statistically significant shorter duration of fever and parenteral antibiotic therapy. Platelet recovery to 20 x 10(9)/L was not significantly influenced by GFs. CONCLUSIONS: These results indicate that only G-CSF accelerates hematological recovery after high-dose chemotherapy and autologous bone marrow transplantation and induces a significant decrease in terms of infection morbidity and duration of hospital stay.