Efficacy of pre-emptively used plerixafor in patients mobilizing poorly after chemomobilization: a single centre experience

A significant proportion of patients with lymphoid malignancies are hard‐to‐mobilize with a combination of chemotherapy plus granulocyte colony‐stimulating factor (G‐CSF) (chemomobilization). Plerixafor is a novel drug used to improve mobilization of blood stem cells. However, it has been studied mainly in association with G‐CSF mobilization. We evaluated the efficacy of ‘pre‐emptive’ use of plerixafor after chemomobilization in patients who seem to mobilize poorly. During a 15 month period, altogether 63 patients with lymphoid malignancies were admitted to our department for blood stem cell collection. Sixteen patients (25%) received plerixafor after the first mobilization due to the low blood (B) CD34⁺ cell counts (n = 12) or poor yield of the first collection (n = 4). The median number of plerixafor injections was 1 (1–3). The median B‐CD34⁺ count after the first plerixafor dose was 39 × 10⁶/L (<1–81) with the median increase of fivefold. Stem cell aphaereses were performed in 14/16 patients (88%) receiving plerixafor and a median of 2.9 × 10⁶/kg (1.6–6.1) CD34⁺ cells were collected with a median of one aphaeresis (1–3). Altogether 13/16 patients mobilized with a combination of chemomobilization and plerixafor received high‐dose therapy with stem cell support and all engrafted. Pre‐emptive use of plerixafor after chemomobilization is efficient and safe and should be considered in poor mobilizers to avoid collection failure. In patients with low but rising B‐CD34⁺ counts, the use of plerixafor might be delayed as late mobilization may occur. Further studies are needed to optimize patient selection and timing of plerixafor.     

Just‐in‐time rescue plerixafor in combination with chemotherapy and granulocyte‐colony stimulating factor for peripheral blood progenitor cell mobilization

Plerixafor, a recently approved peripheral blood progenitor cell mobilizing agent, is often added to granulocyte‐colony stimulating factor (G‐CSF) to mobilize peripheral blood progenitor cells in patients with lymphoma or myeloma who cannot mobilize enough CD34+ cells with G‐CSF alone to undergo autologous stem cell transplantation. However, data are lacking regarding the feasibility and efficacy of just‐in‐time plerixafor in combination with chemotherapy and G‐CSF. We reviewed the peripheral blood stem cell collection data of 38 consecutive patients with lymphoma (Hodgkin's and non‐Hodgkin's) and multiple myeloma who underwent chemomobilization and high‐dose G‐CSF and just‐in‐time plerixafor to evaluate the efficacy of this treatment combination. All patients with multiple myeloma and all but one patient with lymphoma collected the minimum required number of CD34+ cells to proceed with autologous stem cell transplantation (>2 × 10⁶/kg of body weight). The median CD34+ cell dose collected in patients with non‐Hodgkin lymphoma was 4.93 × 10⁶/kg of body weight. The median CD34+ cell dose collected for patients with multiple myeloma was 8.81 × 10⁶/kg of body weight. Plerixafor was well tolerated; no grade 2 or higher non‐hematologic toxic effects were observed. Am. J. Hematol. 88:754–757, 2013. © 2013 Wiley Periodicals, Inc.     

Plerixafor on‐demand combined with chemotherapy and granulocyte colony‐stimulating factor: significant improvement in peripheral blood stem cells mobilization and harvest with no increase in costs

To date, no prospective study on Plerixafor ‘on‐demand’ in combination with chemotherapy and granulocyte colony‐stimulating factor (G‐CSF) has been reported. We present an interim analysis of the first prospective study in which Plerixafor was administered on‐demand in patients affected by multiple myeloma and lymphoma who received high dose cyclophosphamide or DHAP (dexamethasone, cytarabine, cisplatin) plus G‐CSF to mobilize peripheral blood stem cells (PBSC). One hundred and two patients were evaluable for response. A cohort of 240 patients receiving the same mobilizing chemotherapy was retrospectively studied. Failure to mobilize CD34⁺ cells in peripheral blood was reduced by ‘on‐demand’ strategy compared to conventional mobilization; from 13·0 to 3·0% (P = 0·004). Failure to harvest CD34⁺ cells 2 × 10⁶/kg decreased from 20·9 to 4·0% (P = 0·0001). The on‐demand Plerixafor strategy also resulted in a lower rate of mobilization failure (P = 0·03) and harvest failure (P = 0·0008) when compared to a ‘bias‐adjusted set of controls’. Evaluation of economic costs of the two strategies showed that the overall cost of the two treatments were comparable when salvage mobilizations were taken into account. When in combination with cyclophosphamide or DHAP plus G‐CSF, the ‘on‐demand’ use of Plerixafor showed, in comparison to conventionally treated patients, a significant improvement in mobilization of PBSC with no increase in overall cost.     

Stimulation of adrenergic activity by desipramine enhances hematopoietic stem and progenitor cell mobilization along with G‐CSF in multiple myeloma: A pilot study

Hematopoietic stem cell (HSC) release is positively regulated by the sympathetic nervous system through the β3 adrenergic receptor. Preclinical studies have demonstrated that the combination of desipramine and G‐CSF resulted in improved HSC mobilization. Here, we present the results of an open‐label single‐arm pilot study in patients with multiple myeloma undergoing autologous stem cell transplantation (ASCT) to assess the safety and efficacy of desipramine combined with G‐SCF to induce HSC mobilization. The primary endpoint was safety of the combination including engraftment kinetics. The secondary endpoint was the proportion of patients who collected ≥5 × 10⁶ CD34⁺ cells/kg. Outcomes were compared with historical matched controls during the same time period with multiple myeloma mobilized with G‐CSF. All study patients received desipramine 100 mg daily for 7 days, starting 4 days prior to G‐CSF administration (D‐3) and continued taking it along with G‐CSF for a total of 7 days. Six of ten patients enrolled completed the protocol with minimal side effects. All of them achieved the target collection of 5 × 10⁶ CD34 cells/kg in a median of 1.5 apheresis session with two patients needing additional plerixafor (16%), while 11 out of 13 patients (85%) achieved the target of 5 × 10⁶ CD34 cells/kg in the historical control group in a median of 2 apheresis procedures and seven patients needed plerixafor (54%). The combination of desipramine and G‐CSF is safe and signals improved mobilization over G‐CSF alone, providing a possible alternative means of mobilization that needs further investigation.     

Re‐evaluation of progenitor thresholds and expectations for haematopoietic recovery based on an analysis of 810 autologous transplants: Implications for quality assurance

Haematological engraftment was assessed in 804 autologous transplants. Neutrophil recovery occurred in over 99% within 14 d but platelet recovery was delayed beyond this time in 14·8%. Time to recovery was dependent on the progenitor cell dose infused. The minimum CD34⁺ cell threshold adopted in this study (2 × 10⁶/kg) was safe although recovery was faster with a dose >5 × 10⁶/kg. CD34⁺ cell doses of between 1 and 2 × 10⁶/kg were also acceptable if either the granulocyte‐macrophage colony‐forming cell dose exceeded 2 × 10⁵/kg or this dose was due to splitting a higher yield harvest. Prompt neutrophil recovery affords important quality assurance for laboratory processing.     

Allogeneic transplantation using CD34+ selected peripheral blood progenitor cells combined with non‐mobilized donor T cells for refractory severe aplastic anaemia

Allogeneic haematopoietic stem cell transplantation is curative for severe aplastic anaemia (SAA ) unresponsive to immunosuppressive therapy. To reduce chronic graft‐versus‐host disease (GVHD ), which occurs more frequently after peripheral blood stem cell (PBSC ) transplantation compared to bone‐marrow transplantation (BMT ), and to prevent graft rejection, we developed a novel partial T‐cell depleted transplant that infuses high numbers of granulocyte colony‐stimulating factor‐mobilized CD 34⁺ selected PBSC s combined with a BMT ‐equivalent dose of non‐mobilized donor T‐cells. Fifteen patients with refractory SAA received cyclophosphamide, anti‐thymocyte globulin and fludarabine conditioning, and were transplanted with a median 8 × 10⁶ CD 34⁺ cells/kg and 2 × 10⁷ non‐mobilized CD 3⁺ T‐cells/kg from human leucocyte antigen‐matched sibling donors. All achieved sustained engraftment with only two developing acute and two developing chronic GVHD . With a 3·5‐year median follow‐up, 86% of patients survived and were transfusion‐independent. When compared to a retrospective cohort of 56 bone‐marrow failure patients that received the identical transplant preparative regimen and GVHD prophylaxis with the exception that the allograft contained unmanipulated PBSC s, partial T‐cell depleted transplant recipients had delayed donor T‐cell chimerism and relative reduction of 75% in the incidence of acute grade II ‐IV GVHD (13% vs. 52%; P  =  0·010) and of 82% in chronic GVHD (13% vs. 72%; P  =  0·0004). In multivariate analysis, partial T‐cell depleted transplants remained significantly associated with a reduced risk of GVHD . In conclusion, for patients with refractory SAA , this novel transplant strategy achieves excellent engraftment and survival when compared to unmanipulated PBSC transplants and dramatically reduces the incidence of both acute and chronic GVHD .     

Donor lymphocyte infusions and second transplantation as salvage treatment for relapsed myelofibrosis after reduced‐intensity allografting

Thirty myelofibrosis patients (21 males, nine females) with relapse (n = 27) or graft‐rejection (n = 3) after dose‐reduced allografting underwent a salvage strategy including donor lymphocyte infusions (DLIs) and/or second allogeneic haematopoietic stem cell transplantation (HSCT). Twenty‐six patients received a median number of three (range, 1–5) DLIs in a dose‐escalated mode starting with a median dose of 1·2 × 10⁶ (range, 0·003–8 × 10⁶) up to median dose of 40 × 10⁶ T‐cells/kg (range, 10–130 × 10⁶). 10/26 patients (39%) achieved complete response (CR) to DLIs. Acute (grade II‐IV) and chronic graft‐versus‐host (GvHD) disease occurred in 12% and 36% cases. Thirteen non‐responders to DLI and four patients who did not receive DLI due to graft‐rejection or acute transformation of the blast phase underwent a second allogeneic HSCT from alternative (n = 15) or the same (n = 2) donor. One patient (6%) experienced primary graft‐failure and died. Acute (II‐IV) and chronic GvHD were observed in 47% and 46% of patients. Overall responses after second HSCT were seen in 12/15 patients (80%: CR: n = 9, partial response: n = 3). The 1‐year cumulative incidence of non‐relapse mortality for recipients of a second allograft was 6%, and the cumulative incidence of relapse was 24%. After a median follow‐up of 27 months, the 2‐year overall survival and progression‐free survival for all 30 patients was 70% and 67%, respectively. In conclusion, our two‐step strategy, including DLI and second HSCT for non‐responding or ineligible patients, is an effective and well‐tolerated salvage approach for patients relapsing after reduced‐intensity allograft after myelofibrosis.     

Stem cell mobilization in resistant or relapsed lymphoma: superior yield of progenitor cells following a salvage regimen comprising ifosphamide, etoposide and epirubicin compared to intermediate-dose cyclophosphamide

We analysed the factors influencing the efficacy of peripheral blood stem cell (PBSC) collection in patients with lymphoma. Sixty-six patients underwent initial PBSC collection following mobilization with chemotherapy plus recombinant granulocyte colony-stimulating factor (300 μg/d). Patients were mobilized with one of two chemotherapy regimens, either cyclophophamide (3 g/m² or 4 g/m²) (n=50) or ifosphamide, etoposide and epirubicin (IVE; n=16). The target of collecting >2.0×10⁶ CD34⁺ cells/kg was achieved in 43/66 (65%) patients with a median of two apheresis procedures. The IVE plus G-CSF mobilization regimen gave a significantly higher median yield of CD34⁺ cells (8.62 × 10⁶/kg) compared with cyclophosphamide plus G-CSF (3.59 × 10⁶/kg) (P=0.045). The median yield of CD34⁺ cells per leukapheresis was almost twice as high in patients receiving IVE (1.94 × 10⁶/kg) compared to cyclophosphamide (1.03 ×10⁶/kg) (P= 0.035). In a univariate analysis of the factors affecting mobilization, the subtype of lymphoma (high-grade NHL) and the mobilization regimen were the only factors associated with high CD34⁺ cell yield. However, in a multivariate analysis of factors affecting mobilization including age, lymphoma subtype, previous chemotherapy and radiotherapy, only the use of the IVE protocol was predictive of a high yield of CD34⁺ cells. In 13 patients undergoing a second mobilization procedure the use of IVE was associated with a significantly higher yield of CD34⁺ cells compared to cyclophosphamide; three patients who failed cyclophosphamide plus G-CSF mobilization were able to proceed to transplantation following success-ful mobilization with IVE + G-CSF. These results demon-strate that IVE is a highly effective mobilization regimen which is superior to cyclophophamide and has the benefit of being effective salvage therapy for lymphoma patients.     

CD34+ selected stem cell boosts can improve poor graft function after paediatric allogeneic stem cell transplantation

Poor graft function (PGF) is a severe complication of haematopoietic stem cell transplantation (HSCT) and administration of donor stem cell boosts (SCBs) represents a therapeutic option. We report 50 paediatric patients with PGF who received 61 boosts with CD34⁺ selected peripheral blood stem cells (PBSC) after transplantation from matched unrelated (n = 25) or mismatched related (n = 25) donors. Within 8 weeks, a significant increase in median neutrophil counts (0·6 vs. 1·516 × 10⁹/l, P < 0·05) and a decrease in red blood cell and platelet transfusion requirement (median frequencies 1 and 7 vs. 0, P < 0·0001 and <0·001), were observed, and 78·8% of patients resolved one or two of their cytopenias. 36·5% had a complete haematological response. Median lymphocyte counts for CD3⁺, CD3⁺CD4⁺, CD19⁺ and CD56⁺ increased 8·3‐, 14·2‐, 22.‐ and 1·6‐fold. The rate of de novo acute graft‐versus‐host disease (GvHD) grade I–III was only 6% and resolved completely. No GvHD grade IV or chronic GvHD occurred. Patients who responded to SCB displayed a trend toward better overall survival (OS) (P = 0·07). Thus, administration of CD34⁺ selected SCBs from alternative donors is safe and effective. Further studies are warranted to clarify the impact on immune reconstitution and survival.     

Retrospective comparison of mobilization methods for autologous stem cell transplantation in multiple myeloma

The combination of cyclophosphamide and granulocyte‐colony stimulating factor (G‐CSF) has widely been used to mobilize hematopoietic stem cells (HSCs) for autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Recently, however, alternative approaches such as G‐CSF alone or etoposide followed by G‐CSF have been investigated. We, therefore, retrospectively analyzed the effects of these mobilization methods on collection yield and disease outcome in ASCT for MM. We reviewed 146 MM patients from whom we intended to collect stem cells. For mobilization, 67, 58, and 21 patients received cyclophosphamide and G‐CSF, etoposide and G‐CSF, and G‐CSF alone (including nonmyelosuppressive chemotherapy followed by G‐CSF), respectively. Among them, 136 achieved the target number of HSCs (at least 2 × 10⁶/kg). Lower creatinine and higher albumin levels at diagnosis were significantly associated with successful yield. A lower number of infused HSCs, use of the etoposide for mobilization and high ISS were associated with delayed hematopoietic recovery. The mobilization methods did not significantly affect either the successful collection of more than 2 × 10⁶ CD34‐positive cells/kg or PFS after ASCT. G‐CSF alone was sufficient for stem cell mobilization for a single ASCT. The optimal approach to collect HSCs in MM remains to be elucidated. Am. J. Hematol., 2010. © 2009 Wiley‐Liss, Inc.     

Influence of ex vivo purging with CliniMACS CD34+ selection on outcome after autologous stem cell transplantation in non‐Hodgkin lymphoma

The major limitation of autologous stem cell transplantation (auto‐SCT) in non‐Hodgkin lymphoma (NHL) is relapse. Although autologous graft contamination may be a potential cause, prior purging of the autograft remains controversial. Therefore, we retrospectively analysed 56 consecutive patients with NHL receiving auto‐SCT at complete (n = 41) or partial remission (n = 15). Among them, 24 patients underwent autograft manipulation with positive selection of CD34⁺ cells using a CliniMACS device (purged group). Twenty‐five patients had received ≥2 previous chemotherapy regimens before auto‐SCT. After a median follow‐up of 41·4 months, transplant‐related mortality was observed only in unpurged group (n = 2; 3·6%). The 3‐year overall survival (91·7% vs. 56·1%, P = 0·009) and progression‐free survival (78·7% vs. 53·1%, P = 0·034) favoured CD34⁺ purification. While neutrophil recovery was similar, platelet recovery was delayed in the purged group. Cytomegalovirus reactivation was predominantly observed in the purged group, although no other clinically unmanageable infectious complications occurred. Although this study has the inevitable limitations of heterogeneity in previous treatment and NHL subtypes, and a small number of patients analysed, the high survival rate in the purged group may suggest the need for prospective randomized trials to determine the role of CD34⁺ purification in auto‐SCT for NHL.     

Comparison of rhG–CSF primed bone marrow and blood stem cell autografts: an analysis of engraftment in malignant lymphomas and solid tumours

Abstract: Many studies have documented faster engraftment after transplantation with peripheral blood stem cells (PBSC) compared to bone marrow (BM) stem cells. Most comparisons, however, have been between unprimed BM and primed PBSC. We have collected engraftment data on 39 patients from 4 Danish centres and compared G–CSF primed BM with G–CSF primed PBSC in malignant lymphoma and solid tumours. In the lymphoma group 6 BM transplants were compared with 8 PBSC transplants, whereas in the testicular cancer group 16 BM transplants were compared with 9 PBSC transplants. In the lymphoma group, the time to platelet engraftment (platelets >20times10⁹/l unsupported) was median 15 d in PBSC transplants and median 34 d in BM transplants (p=0.003). In the solid tumour patients the difference in time to platelet engraftment was 11 and 18 d in PBSC and BM transplants, respectively (p<0.0001). In an attempt to explain this difference we performed CD34⁺ subset analysis of BM and PBSC. This analysis revealed a higher content of lineage restricted cells (CD34⁺CD61⁺ and CD34⁺GlyA⁺) in PBSC compared to BM. In conclusion, G–CSF mobilized PBSC seems to result in faster engraftment than G–CSF primed BM, which could be explained by an increased number of lineage specific progenitors in PBSC compared to BM.     

Determination of peripheral blood stem cells by the Sysmex SE‐9500

The Sysmex SE‐9500 automated haematology analyser provides an estimate of immature cells, referred to as ‘haematopoietic progenitor cells’ (HPC). The aim of this study was to evaluate the reliability and usefulness of the SE‐9500 HPC parameter as compared with the CD34 + cell count and to determine whether the HPC count was of value in predicting the optimal harvesting time for peripheral blood stem cells (PBSC). Studies were performed on 112 samples from 21 patients with haematological malignancies and 13 healthy donors undergoing progenitor cell mobilisation. Coefficients of variation for the HPC count were 30%, 23.8%, 12.4% and 8.3% respectively for samples with low (4 × 10⁶/l), medium (13 × 10⁶/l), high (250 × 10⁶/l) and very high (2413 × 10⁶/l) counts. There was good linearity for HPC measurement in both peripheral blood (PB) and purified CD34 + cell suspensions (r > 0.995), and no detectable carryover was observed. There was an acceptable correlation between HPC and CD34 + cell counts for PB samples (r=0.669) and for CD34 + cell suspensions (r=0.859). Analysis of purified CD34 + cells using the SE‐9500 HPC mode revealed that they appear both in the blast cell area and the immature granulocyte area of the analyser cell display. Quantitation of CD34 + cells and HPC during PBSC mobilisation showed good agreement between these parameters with regard to the optimal time for PBSC harvesting. These findings suggest that HPC counting with the Sysmex SE‐9500 may be clinically useful for optimising the timing of PBSC collection.     

Circulating myeloid‐derived suppressor cells correlate with clinical outcome in Hodgkin Lymphoma patients treated up‐front with a risk‐adapted strategy

In the attempt to find a peripheral blood biological marker that could mirror the dysregulated microenvironment of Hodgkin Lymphoma (HL), we analysed the amount of myeloid‐derived suppressor cells (MDSC), including the three main sub‐types (monocytic, granulocytic and CD34 + fraction). The absolute MDSC count was investigated in 60 consecutive newly diagnosed HL patients and correlated with clinical variables at diagnosis and outcome. Patients received standard‐of‐care chemotherapy with the exception of interim fluorodeoxyglucose positron emission tomography (PET‐2)‐positive patients, who were switched early to a salvage regimen. All MDSC subsets were increased in HL patients compared to normal subjects (P < 0·0001) and were higher in non‐responders. However, a strong prognostic significance was limited to immature (CD34⁺) MDSC. A cut‐off level of 0·0045 × 10⁹/l for CD34⁺MDSC resulted in 89% (95% confidence interval [CI] 52–99%) sensitivity and 92% (95% CI 81–98%) specificity. The positive predictive value to predict progression‐free survival was 0·90 for PET‐2 and 0·98 for CD34⁺MDSC count; the negative predictive value was 0·57 for PET‐2 and 0·73 for CD34⁺MDSC. PFS was significantly shorter in patients with more than 0·0045 × 10⁹ CD34⁺MDSC cells/l at diagnosis and/or PET‐2 positivity (P < 0·0001). In conclusion, all circulating MDSC subsets are increased in HL; CD34⁺MDSC predict short PFS, similarly to PET‐2 but with the advantage of being available at diagnosis.     

Cord blood transplantation in Western Australia

Background/Aims: Thirty‐one umbilical cord blood transplants performed in Western Australia were retrospectively examined in order to document local experience and relevant prognostic factors. Three cord units were from human leucocyte antigen‐matched siblings and the remainder were unrelated single (n= 22) or double (n= 6) cord blood transplants. Methods: Twenty patients were transplanted for malignant conditions and 11 for non‐malignant conditions. Cord units contained a median of 5.6 × 10⁷ total nucleated cells/kg and 1.4 × 10⁵ CD34+ cells/kg. Cumulative incidence of neutrophil engraftment was 76% at day 60. Results: Of those who did not engraft, two patients remain alive following subsequent allogeneic bone marrow transplant. There were no deaths caused by graft‐versus‐host disease. Overall survival at median follow up of 28 months was 62%. Two year overall survival was influenced by type of disease (non‐malignant = 91 ± 9% vs malignant = 41 ± 13%, P= 0.005), total nucleated cell dose (>3.5 × 10⁷/kg = 87 ± 9% vs <3.5 × 10⁷/kg = 34 ± 15%, P= 0.01) and CD34 dose (>1.7 × 10⁵/kg = 92% vs <1.7 × 10⁵/kg = 46%, P= 0.04). Age and human leucocyte antigen match did not influence survival. Four relapses occurred, all of which were fatal. Conclusion: Cord blood transplantation for malignant and non‐malignant disease is practised in Western Australia and outcomes are satisfactory. Trends and techniques in cord blood transplantation in this state are comparable with those observed nationally and overseas. Although numbers are small, cell dose appears to be predictive of overall survival.     

Monitoring of Peripheral Blood CD34+ Cell Counts on the First Day of Apheresis Is Highly Predictive for Efficient CD34+ Cell Yield

Abstract: The purpose of this study was to evaluate the correlation of preleukapheresis circulating CD34+ cells/μL, white blood cells (WBC), and platelet counts on the first day of apheresis with the yield of collected CD34+ cell counts in 40 patients with hematological malignancies (n = 29) and solid tumors (n = 11). The median numbers of apheresis cycles, numbers of CD34+ cells, peripheral blood (PB) mononuclear cells, and total nucleated cells collected were 2 (range, 1–4), 5.5 × 10⁶/kg (range, 0.05–33.78), 2.59 × 10⁸/kg (range, 0.04–20.68), and 7.36 × 10⁸/kg (range, 0.15–28.08), respectively. There was a strong correlation between the number of preleukapheresis circulating CD34+ cells/μL and the yield of collected CD34+ cells per kilogram (r = 0.962, p < 0.001). The threshold levels of PB CD34+ cell/μL to obtain ≥1 × 10⁶/kg and ≥2.5 × 10⁶/kg CD34+ cell in one collection were 12/μL and 34/μL, respectively. Fifteen of 17 (88%) patients who had ≥34 CD34+ cells/μL in the PB before collection reached the level of ≥2.5 × 10⁶/kg in a single apheresis. Despite a low r value, WBC and platelet counts on the first day of apheresis also correlated with the yield of collected daily CD34+ cells per kilogram (r = 0.482, p < 0.01 and r = 0.496 p < 0.01, respectively). These data suggest that preleukapheresis circulating CD34+ cells/μL correlated significantly better with the yield of collected CD34+ cells than WBC and platelet counts on the first day of apheresis. Using a value of 34/μL preleukapheresis circulating CD34+ cells as a guide for the timing of peripheral blood stem cells collections can be time saving and cost‐effective.     

Intensification treatment based on early FDG‐PET in patients with high‐risk diffuse large B‐cell lymphoma: a phase II GELTAMO trial

We conducted a multicentre, phase II study of interim positron emission tomography (PET) as a guide to risk‐adapted therapy in high‐risk patients with newly diagnosed diffuse large B‐cell lymphoma (DLBCL). Patients achieving negative fluorodeoxyglucose (FDG)‐PET after three courses of R‐MegaCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) received three additional courses, whereas PET‐positive patients received two courses of R‐IFE (rituximab, ifosfamide, etoposide) followed by BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous stem‐cell transplantation. The primary endpoint was progression‐free survival (PFS). 71 patients (median age 55 years, range 25–69) were enrolled. With a median follow‐up of 42·8 months (range 7·2–58·4), the estimated 4‐year PFS and overall survival (OS) were 67% and 78%, respectively, for the global series. Patients in complete remission after interim PET (N = 36) had significantly better 3‐year PFS than those with partial response (N = 30) [81% vs. 57%, Hazard ratio (HR) = 2·6, 95% confidence interval (CI) = 1·02–6·65] but not a statistically significant longer OS. A retrospective PET central review was done for 51 patients. According to semiquantitative analysis, 3‐year PFS (81% vs. 33%; HR = 6·9, 95% CI = 2·35–20·6) and OS (95% vs. 33%, HR = 19·4, 95% CI = 3·89–97·0) were significantly better for negative than for positive interim PET patients. Early PET assessment is valuable for risk stratification in DLBCL; for this purpose semiquantitative evaluation is a better predictor than visual criteria.     

Successful collection of peripheral blood progenitor cells in patients with acute myeloid leukaemia following early consolidation therapy with granulocyte colony-stimulating factor-supported high-dose cytarabine and mitoxantrone

We evaluated the feasibility of collecting peripheral blood progenitor cells (PBPC) in patients with acute myeloid leukaemia (AML) following two cycles of induction chemotherapy with idarubicin, cytarabine and etoposide (ICE), and one cycle of consolidation therapy with high-dose cytarabine and mitoxantrone (HAM). Thirty-six patients of the multicentre treatment trial AML HD93 were enrolled in this study, and a sufficient number of PBPC was harvested in 30 (83%). Individual peak concentrations of CD34⁺ cells in the blood varied (range 13.1–291.5/μl; median 20.0/μl). To reach the target quantity of 2.5 × 10⁶ CD34⁺ cells/kg, between one and six (median two) leukaphereses (LP) were performed. The LP products contained between 0.2 × 10⁶ and 18.9 × 10⁶ CD34⁺cells/kg (median 1.2 × 10⁶/kg). Multivariate analysis showed that the white blood cell count prior to HAM and the time interval from the start of HAM therapy to reach an unsupported platelet count > 20 × 10⁹/l were predictive for the peak value of CD34⁺ cells in the blood during the G-CSF stimulated haematological recovery. In 16 patients an intraindividual comparison was made between bone marrow (BM) and PBPC grafts. Compared to BM grafts, PBPC grafts contained 14-fold more MNC, 5-fold more CD34⁺ cells and 36-fold more CFU-GM. A CD34⁺ subset analysis showed that blood-derived CD34⁺ cells had a more immature phenotype as indicated by a lower mean fluorescence intensity for HLA-DR and CD38. In addition, the proportion of CD34⁺/Thy-1⁺ cells tended to be greater in the PBPC grafts. The data indicate that sufficient PBPC can be collected in the majority of patients with AML following intensive double induction and first consolidation therapy with high-dose cytarabine and mitoxantrone.     

Mobilization and harvesting of peripheral blood stem cells in pediatric patients with solid tumors

Survival of patients with high‐risk pediatric solid tumors has improved with the introduction of a high‐dose chemotherapy regimen and autologous stem cell rescue. Here, we present our data regarding the evaluation of the efficacy and safety of hematopoietic stem cell mobilization and harvesting in children with solid tumors. From November 2002 to March 2010, 85 children underwent autologous peripheral blood stem cell collection; 35 (41.1%) of them weighed less than 20 kg and were diagnosed with neuroblastoma, Wilms' tumor, medulloblastoma, yolk sac sarcoma, or non‐Hodgkin's lymphoma. The mobilization regimens included disease‐specific chemotherapy plus granulocyte colony‐stimulating factor in most of the patients. The median age and weight at the time of apheresis was 36 months and 13.5 kg, respectively. Large‐volume leukapheresis was performed with the aim of reducing the psychological and financial impact of leukapheresis by reducing the number of procedures while collecting a large number of cells. The median number of mobilization and leukapheresis procedures per case was one. The pre‐apheresis CD34+ cell count ranged from 2 to 845 µL, with a median of 24 µL. A median of four patient blood volumes was processed per procedure, lasting 279 min (range, 113–420 min). A radial catheter was used for harvesting in 35 procedures (71.4%). The median yield of CD34+ cells was 6.6 × 10⁶/kg per patient. The targeted dose of 5 × 10⁶/kg CD34+ cells was realized in 80% of patients. The tolerance of peripheral blood stem cell collection in our patients was good. In conclusion, the collection of peripheral blood stem cells is an effective and safe procedure, even when conducted on the youngest children.     

Donor lymphocyte infusion and methotrexate for immune recovery after T‐cell depleted haploidentical transplantation

CD34+ cell selection minimizes graft‐versus‐host disease (GVHD) after haploidentical donor stem cell transplant but is associated with slow immune recovery and infections. We report a Phase I/II study of prophylactic donor lymphocyte infusion (DLI) followed by methotrexate (MTX) GVHD prophylaxis after CD34‐selected haploidentical donor transplant. A prophylactic DLI was given between day +30 and +42. Rituximab was given with DLI for the last 10 patients. The goal of the study was to determine a DLI dose that would result in a CD4+ cell count > 100/µL at Day +120 in ≥ 66% of patients with ≤ 33% grade II‐III, ≤ 17% grade III, and no grade IV acute GVHD by Day +180. Thirty‐five patients with malignant (n = 25) or nonmalignant disease (n = 10) were treated after CD34‐selected haploidentical donor peripheral blood stem cell transplant. The DLI dose of 5 × 10⁴/kg met the CD4/GVHD goal with 67% of patients having CD4+ cells > 100/µL and 11% grade II‐IV acute GVHD. The cumulative incidence of chronic GVHD was 16%. Fatal viral and fungal infections occurred in 11%. The 2 year estimated overall survival was 69% and the relapse rate was 14% for patients in remission at transplant. There was no effect of NK alloreactivity on relapse. Nine of ten patients at the target DLI dose cohort of 5 × 10⁴/kg are alive with median follow‐up of 18 mos (range 6‐29). Delayed prophylactic DLI and MTX was associated with promising outcomes at the target DLI dose. This trial was registered at clinicaltrials.gov , # NCT01027702.