During the last 25 years, improvement in survival for young children with acute lymphoblastic leukaemia (ALL) has been striking: children aged 1 to 9 years have the best outcome. However, children and adolescents aged 10 to 20 years have a markedly worse outcome, which is associated – in part – with genetic abnormalities, a lower incidence of favourable genetic abnormalities such as TEL/AML1 and hyperdiploidy, and a higher incidence of T-cell leukaemia.

Adolescents are less likely to have access to healthcare, are more likely to see providers who are not part of research institutions, and are less likely to be referred to or to join clinical trials, all of which may contribute to worse outcomes. Adolescents are treated by both adult and pediatric teams, following either adult or pediatric protocols. The type of team by which adolescents are treated (pediatric teams, or “combined” teams) may also impact the outcome. An unpublished survey by the EBMT (Dini) showed that 67% of patients aged 14-18 years old who received allogeneic hematopoietic stem cell transplantation (HSCT) for 2^nd CR ALL from 1996 to 2005 that was reported to the EBMT registry had been treated by pediatric teams only, while the remaining 33% had been treated by adult teams [1].

Recent European studies have shown better outcomes in adolescents treated with pediatric protocols as compared to those treated with adult ones [2-5].
Adolescents should be referred to research treatment teams that have experience in the management of peediatric ALL, and they should be enrolled in international cooperative studies.  Molecular, genetic, and proteomic evaluation may cast further light on the causes of the rather striking decrease in survival that is seen as the patient progresses from childhood to adolescence.

Keywords

acute lymphoblastic leukemia, adolescents, pediatric ALL protocols, allogeneic hematopoietic stem cell transplantation, allo-HSCT

Background

ABO incompatibility between donor and recipient is currently considered one of the risk factors for immune-mediated complications, which can influence the outcome of allogeneic hematopoietic stem cell transplantation (allo-SCT).

Patients and methods

We analyzed 140 consecutive allo-HSCT recipients. 124 patients had HLA-compatible donors (39 related and 85 unrelated) and 16 patients had haploidentical donors. Fifty-nine of the donor–recipient pairs were ABO-identical, while 34 had minor incompatibility, 35 major incompatibility, and 12 bidirectional incompatibility. Seventy-eight patients received bone marrow (BM), 46 peripheral blood stem cells (PBSC), and 16 stem cells from both sources. Conventional myeloablative conditioning was used in 64 patients and non–myeloablative regimens in 78 patients. In both groups the same regimen of graft–versus–host disease (GVHD) prophylaxis was administered. In major ABO incompatibility SCT donor stem cells were depleted of RBC (6% hydroxyethyl starch sedimentation), in cases of minor incompatibility donor incompatible plasma was removed, and in cases of bidirectional incompatibility both methods were used.

Results

In all the study groups, we observed no cases of acute hemolysis after PBSC transfusion and only 2 cases after BM transfusion. Engraftment of leukocytes, neutrophils, and platelets was not altered in any of the groups (р=0.45).  Delayed RBC engraftment was more frequent in patients with ABO-incompatible SCTs (р=0.04). There were 4 cases of delayed hemolysis. Incidence and severity of GVHD was higher in the ABO-incompatible allo-SCT group (р=0.005).

Conclusions

ABO incompatibility between donor and recipient can cause acute and delayed hemolysis and it is a risk factor in the development of GVHD. It can delay RBC engraftment, but has no influence on other cell lines. Adequate prophylactic measures allow us to keep the incidence of acute hemolysis low.

Keywords

ABO incompatibility, PBSC, GVHD, engraftment

Between January 1999 and August 2008, a total of 272 newly diagnosed patients (pts) up to 18 years of age with ALL were treated according to the COALL-Saint-Petersburg-92 protocol (COALL-S-Pb-92). Since August 2008, the pediatric oncohemathological clinics of St. Petersburg have been affiliated with the all-Russian study Moscow-Berlin 2008.

Methods

Protocol COALL-S-Pb-92 is a modification of the German protocol COALL-92. The intensive phase of treatment lasted  5.5 months in the low risk (LR) group  and 8 months in the high risk (HR) group and consisted of 4 parts: induction, consolidation, CNS-treatment and reinduction. It was followed by maintenance treatment until 2 years from the date of diagnosis. Treatment of presymptomatic CNS disease consisted of i.th. MTX; cranial irradiation (12 Gy) was given additionally  to HR pts with T-ALL and/or primary hyperleukocytosis.

Pts were stratified into LR (n=129, 47%) or HR (n=143, 53%) groups. The criteria for HR were: initial white blood count ≥ 25000/l, primary CNS and/or mediastinal involvement, Т-cell and pre-pre-B-cell immunophenotype, an age ≥ 10 years, Ph–chromosome positivity, and failure to achieve remission at day 28 from the beginning of treatment.

Results

266 pts (98%) achieved complete remission. 6 HR pts died during induction (hemorrhagic and infectious complications, progression of leukemia). There was only the one late responder, no non-responders. 18 pts died of infectious complications while in remission. 47 (17.7%) patients relapsed: 12.4% in the LR group and 22.6% in the HR group. Non-lethal complications – like mucositis, hepatotoxicity, hemorrhagic and infectious complications – were more frequent and severe in HR–group pts. After an observation time of 10 years, the estimate for EFS of all 272 valuable patients is 64.8±3.4% (LR 74.7±4.4%, HR 55.9±4.9%), the estimate of probability of RFS is 75.9±3.4% (LR 82.4±4.1%, HR 69.6±4.8%) and probability of overall survival is 76.0±3.1% (LR 87.5±3.5%, HR 65.3±5.0%).

Conclusions

Treatment results based on the COALL-92 protocol have demonstrated an obvious improvement in comparison with previous results of leukemia chemotherapy in children in St. Petersburg. We are going to continue to follow up our COALL patients in order to be able to compare treatment results in different age and risk groups as well as long-term survival and treatment sequela with different treatment strategies.

Keywords

acute lymphoblastic leukemia, children, intensive chemotherapy

The Russian multicenter APL-2003 protocol for pediatric APL demonstrated a non–inferior outcome compared with the APL-93/98 studies despite a reduction of ATRA to 25 mg/m² and cumulative anthracycline dose to 405 mg/m²: at a median follow up of 35 mo the EFS and OS were 0.79±0.6 and 0.93±0.3. Seven relapses (11.9%) occurred out of 61 patients (pts) at a median of 21 (4–35) mo. Second remission was induced with diverse therapy (Table 1) and consolidated with 14 ATO at 0.15 mg/kg per day;
in 1 pt gemtuzumab ozogamicin (GO) at 6 mg/m² was added to ATO. All pts achieved 2^nd hematological remission and PML/RARα negativity in bone marrow either after induction (3 pts) or after consolidation (4 pts). HDAraC + G–CSF were used for additional “in-vivo purging” and PBSC mobilization. Harvesting was successful in all pts: а median of CD34+ dose 17 (8–40) х 10⁶/kg was achieved after single apheresis. In all cases, apheresis product proved to be PML/RARα negative. AHSCT was performed in 6 pts after conditioning with HDAraC + Mel180 mg/m² in 4 pts, Bu12mg/kg + Mel 140 mg/m² in 1 pt and Treosulfan 42 mg/m² + Mel140 mg/m² in 1 pt. All pts engrafted at a median of 16 (12–25) d with minimal transplant-related toxicity. Three pts received GO on day +100 after ASCT with minimal toxicity. Two pts with skin involvement received complementary electron beam skin irradiation. At a median of 26 mo 6 pts continued in molecular remission and 1 pt experienced 2^nd relapse. We conclude that children with relapsed APL can be treated effectively with chemotherapy, ATO, and ASCT.

Keywords: promylocytic leukemia, arsenic trioxide, autologous hematopoietic stem cell transplantation

In patients with high-risk acute leukemia (AL) hematopoietic stem cell transplantation (HSCT) is an essential part of the treatment strategy. Current trends in HSCT suggest the use of myeloablative conditioning in leukemia patients. However, myeloablative preparative regimens are associated with a risk of treatment-related mortality. Given that the use of reduced intensity conditioning regimens (RIC) decreases TRM rates but appear to be associated with a higher incidence of relapse than observed with more intensive regimens. Data of 109 HSCT performed in patients with acute leukemia were analyzed with purpose to compare outcomes of RIC HSCTs (55 pts) and meyloablative preparative regimens (54 pts). Disease status at the time of transplantation was 1 or 2 CR.

There was no statistically significant difference in OS between RIC HSCT and standard preparative regimen (OS after RIC was 45% versus 46% after myeloablative conditioning). Moreover, statistically significant improvement of OS was noted in patients with ALL. Seven years OS after RIC HSCT was 58% (n=22) versus 32 % (n=34) after myeloablative conditioning. In pediatric ALL 7 years OS after RIC HSCT was 64% (n=14) versus 43% (n=23) after myeloablative conditioning. However, there was no difference in EFS after HSCT performed in pediatric ALL (37% (n=14) after RIC versus 39% (n=23) after myeloablative conditioning).      
Patients after RIC HSCT showed faster engraftment, therefore had lower rate of bacterial complications and received fewer haemotransfusions.

According to our data RIC HSCT is better tolerated by patients, has more favorable short term outcomes than more intensive regimens. Analyzes of HSCT outcomes in pediatric ALL revealed significant improvement in OS after RIC, nevertheless there was no difference in term of EFS. These results encourage us to continue investigations on RIC use. Our researches focus on post HSCT relapse prophylaxis by means of immunadoptive and targeted therapy.

Keywords: acute leukemia, reduced-intensity conditioning, immunoadoptive therapy

Aim

To analyze the results of SyBMT in patients (pts) with leukemia.

Materials and methods

We included 11 pts: 7 CML (6 – CP, 1 – AP) and 4 AL (3 in CR, 1 in relapse): M/F 7/4, average age 24.5 years (13–39). In all cases myeloablative conditioning (BU 16 mg/kg+Cph 120 mg/kg) was used. Morphological, cytogenetic and molecular (FISH, RT PCR) investigations were performed.

Results

Of the 7 CML pts, 4 are alive: 2 have been in complete molecular remission (CMR) for 143 and 206 mo, while a third has been in complete cytogenetic remission (CCR) for 17 mo. During the first 3 mo after BMT, the third patient had a very weak expression of the BCR/ABL gene according to an RT PCR. In 6 mo he was negative according to an RT PCR and in 13 and 16 mo BCR/ABL was determined again (0.05–0.04%) accordingly. One pt with AP CML has been in a chronic phase for 136 mo, while 3 pts relapsed and died. Of the 4 pts with AL, 3 are alive – all 3 were in CR before BMT. One pt remained in CMR and 2 pts achieved only CCR, but the persistence of inv (16) – which was detected before BMTaccording to an RT PCR – was revealed. Therefore, of the initial 11 pts, 7 (64%) are alive: 6 of who are in CCR – of which 3 are in CMR. At the same time, 3 pts with CCR – 1 CML and 2 AL – have MRD according to an RT PCR; FISH was negative in all cases.

Conclusion

After SyBMT, long survival of pts is possible in the majority of cases where CCR has been achieved. The RT PCR method was the most informative for the diagnosis of MRD, which was recognized in 3 of the 6 pts. We previously published our first encouraging results of using immunomodulatory therapy after autological BMT: the relapse rate decreased twice in treated pts. At that time a question came up: Is it necessary to treat patients after SyBMT, especially those with MRD? Recently, the use of immunomodulatory therapy after SyBMT was initiated in our clinic: IFN-α in CML and IFN-α + ATRA or IL2 in acute AL. The results will be evaluated in the future.

Keywords

syngeneic bone marrow transplantation, graft-versus-leukemia effects, GVL, acute leukemia, AL, chronic myeloid leukemia, CML, minimal residual disease, MRD

Purpose

We presume that a combination of CT and epigenetic therapy (ET) might improve the results in pediatric AML.Methods: Between October 2006 and August 2008, 42 children with AML were enrolled in the study: 25 boys (59.5%) and 17 girls (40.5%); the mean age was 8.3±0.8 ys. Seven pts (16.7%) were found to be standard risk (SR), 15 (34.7%) intermediate risk (IR), and 20 (48.6%) high risk (HR). Standard cytogenetics was performed in 32 patients.

Treatment was carried out according to the NII-DOG-AML 2007 protocol. CT for SR consisted of induction (AIE), consolidation (Ara-C 75mg/m²/d 4 days N4 every week, daunomycin 30mg/m²/m N4 every week, and 6–MP 60mg/m²/d days 1–28), and two courses HAE. For pts with IR and HR, CT had 4 courses: AIE, HAM in timing as induction, and postinduction (FLAG, HAE). ET consisted of ATRA 25mg/m²/d+valproic acid (VPA) 25mg/kg/d. Children with SR got VPA during maintenance until the seventy-eighth week and ATRA for 14 days every 14 days. Pts with IR and HR got VPA during all treatment for 18 mo and ATRA during the first 45 days and for 14 days with every consecutive CT course.

Results

Response was assessed on day 15. CR (M-1) was observed in all 7 SR pts, in 14 IR pts (93.3%), and in 14 HR pts (70%); PR (M-2) was observed in 1  IR pt (6.7%). All 4 children who did not respond on day 15 were in HR. After induction, CR was seen in 39  pts (92.9%). CR was not observed in 3 pts: 1 died from invasive aspergillosis, and 2 never got into CR. The 29 mo EFS was 57.2±8.3%, median follow up 18.8±1.8 mo, DFS 67.7±8.3%, and median follow up 21.1±1.8 mo. ET did not lead to any severe complications.

Conclusion

Chemotherapy combined with epigenetic treatment lead to complete remission in 39 out of 42 pts with AML without any extra toxicity. These results allow us to go on with this study.

Keywords

childhood acute myeloid leukemia, chemotherapy, epigenetic therapy

Background

Allogeneic hematopoietic stem cell transplant (allo HSCT) is a curative approach for children with hematological malignancies but is associated with high treatment-related morbidity and mortality. A conditioning regimen (CR) with reduced toxicity is a potential option used in these cases. Treosulfan is an alkylating agent with high antileukemic, myeloablative activity and low toxicity. We compared the efficacy and toxicity of two conditioning regimens in allo HSCT: treosulfan (TREO)+cyclophosphamide (CY) (first group) and busulfan (BU) +CY (second group).

Patients and methods

The first group – with a follow-up from Feb. 2004 to Nov. 2007 – had 11 patients (pts): 6 boys and 5 girls; a median age of 9 y.o.; ALL – 10 pts and AML – 1 pt;  CR: TREO 30–42 g/m² and CY 120mg/kg; HSC donors: 2 matched related donors (MRD) and 9 matched unrelated donor (MUD). The second group – with a follow-up from Nov 2000 to Nov 2006 – had 31 pts: 19 boys and 12 girls; a median age of 12 y.o.; AML – 7 pts, ALL – 24 pts; HSC donors: 11 MRD and 20 MUD; CR: BU 16 mg/kg and CY 120mg/kg. Prophylaxis for aGVHD: CsA+MTX. Unrelated allo-HSCT pts received ATG (“Pfizer”) 60 mg/kg.

Results

First vs second group: engraftment on day +17 vs +21, primary non-engraftment 0% vs 6% (p<0.05), hemorrhagic complication 18 vs 68% (p<0.05). Common toxicity criteria (CTC) II/IV: VOD 0% vs 3% (p<0.05), mucositis 18% vs 68% (p<0.05), neurology symptoms 9% vs 23% (p<0.05), hepatic toxicity 18% vs 26%. AGVHD III/IV 36% vs 20%, relapse 27% vs 29%. Three-year overall survival (OS) 37% vs 40%, respectively.

Conclusion

A treosulfan-based conditioning regimen is well tolerable, safe, efficient, and can be used in heavily-pretreated children with severe complications after previous chemotherapy; though in comparing the efficacy of both regimens, there are no differences. 

Keywords

allo HSCT, toxicity, efficacy, treosulfan, busulfan

In the period 1.1.2000–31.12.2007 129 patients with ALL under 66 years who received treatment with curative intent were registered in Norway (B-ALL 103 T-ALL 26). The median age was 38,6 years (15,6–65,9 years). The majority (110 patients) were treated with a common national protocol consisting of prednisone, vincristine, asparginase, doxorubicin and cyclophosphamide as induction. Consolidation was daunorubicin, cytarabine and  thioguanine, followed by methotrexate i.v. and mercaptopurine per os. Maintenance was prednisone, vincristine and doxorubicin i.v. followed by methotrexate and mercaptopurine per os, given as part of a 3 months cycle repeatedly for 3 ½ years. CNS prophylaxis consisted of i.t. injections of methotrexate. Patients with high risk ALL were elegible for allogenous stem cell transplantation in CR 1.

In all 82,9% reached CR. For patients < 40 years and for patients ≥ 40 years CR rates were 91,4% and 72,9%, respectively. Nine patients received SCT in CR 1 and 2 patients received SCT in CR 2. Five year overall survival was 48,6% (SD 43,0%–54,2%), for patients < 40 years 54,9% (SD 47,3%–62,5%) and for patients ≥40 years 34,9% (SD 26,1%–43,7%).

Keywords

acute lymphatic leukemia, chemotherapy, stem cell transplantation, remission frequency, overall survival

Allogeneic stem cell transplantation is an efficient treatment of malignant hematological disorders but considerable morbidity and mortality limit its use. To reduce complications, conditioning regimens with reduced extramedullary toxicity compared to standard regimens – but with a strong cytotoxic effect on hematopoietic cells – can be used. The combination of treosulfan (14 g/m² x 3) and fludarabine (30 mg/m² x 5) is such a regimen. It has been used in clinical studies as well as in routine practice in patients too fragile to be given conventional conditioning. In a phase II study in MDS, 45 patients were transplanted using this conditioning. The median age was 50 (range 22–63) years. Of the donors 33% were related and 67% unrelated (MUD). The IPSS risk groups were 7% low, 44% Int-1, 31% Int-2, and 18% high. GVHD prophylaxis was CsA+MTX, and ATG in case of MUD. The graft was PBPC in 89% and BM in 11%. The median follow-up was 25 (range 12–41) months. The median times to neutrophil (> 0.5 x 10⁹/l) and platelet (> 20 x 10⁹/l) engraftment were 18 and 17 days. The cumulative incidence (CI) of complete donor chimerism was 73% on day +28 and 93% on day +100. The toxicity was very modest. The CI of gr II–IV aGVHD was 24% and that of gr III–IV 16%. The CI of cGVHD at 2 years was 59% and that of extensive cGVHD 28%. The CI of non–relapse mortality was 9% at 100 days and 17% at 2 years, and that of relapse/progression 16% at 2 years. The Kaplan-Meier estimates of OS and DFS at 2 years were 71% and 67%. These data confirm the favourable safety and efficacy of treosulfan-based conditioning in MDS. Because of the modest toxicity, allogeneic transplantation using treosulfan-based conditioning can be offered to many patients considered too fragile to receive conventional conditioning.

Keywords

allogeneic stem cell transplantation, reduced-toxicity conditioning, myelodysplastic syndrome, treosulfan, fludarabine

Introduction

For the last 20 years allo–HSCT has been one of the most effective treatments for different hematological malignancies. Hematopoietic chimerism analysis is an important method of monitoring the post-allo-HSCT outcome.

Patients and methods

In the study we included 142 patients with different hematological malignancies allografted between October 2002 and October 2008. The chimerism status was assessed by analyzing short tandem repeat polymorphisms.

Results

Overall survival in patients with complete donor chimerism on day +28 after allo-HSCT was 55% and 17% in patients with mixed chimerism or an absence of chimerism on the same day (p=0.0124). Similar results were observed by analyzing chimerism on day +60 following allo-HSCT. There were no significant differences in overall survival depending on chimerism value on day +28 and +60 in patients with myeloablative and nonmyeloablative conditioning regimen.

Of the patients with mixed chimerism or an absence of chimerism on day +28 after allo-HSCT, 67% had disease relapse, while 33% remained in remission (p=0.023).

Conclusions

Complete donor chimerism on day +28 and day +60 after allo-HSCT is associated with better prognosis. Mixed chimerism at day +28 after allo-HSCT is associated with an increased risk of relapse.

Keywords

chimerism, allo-HSCT, relapse, outcome

Allogeneic stem cell transplantation (allo-SCT) is an important therapeutical approach for patients with different malignant and non–malignant disorders. However, the failure to find a proper donor match for all recipients restricts the procedure in most cases due to higher graft-versus-host disease (GVHD) rates. Currently, reports comparing the clinical efficacy of different antithymocyte globulin (ATG) brands regarding their post–transplant prophylaxis value after allo-SCT from HLA-mismatched donors are limited. In this report we have evaluated the outcomes of 24 patients with different hematological malignancies who underwent unrelated SCTs during a period from 2005 to 2008.

The patients’ median age was 15 years (range, 1–48). All transplants had been performed with unrelated grafts carrying one or more mismatches in HLA-А, -В, -С, -DRB1, -DQB1 loci. The post–transplant prophylactic regimens were based on a combination of either cyclosporine A with methotrexate or CellCept with tacrolimus. All transplanted patients received peripheral blood stem cells as stem cell source. The median CD34⁺ cell dose was 6.6 х10⁶/kg bw (range, 1–18). Myeloablative and nonmyeloablative preparative conditioning had been used in 37% and 63% of all transplants, respectively. Depending on the brand of ATG being used, all patients were subdivided in two groups. The first group (n=7) received thymoglobulin (cum. dose 7.5 mg/kg), while the second group (n=17) ATGAM (cum. dose 60 mg/kg). Both groups were comparable concerning the sex and AB0–blood group mismatch between donor and recipient. 

Neutrophil engraftment rates were similar in both groups: day +15 (range, 13–25) in the thymoglobulin group and day +16 (range, 11–22) in the ATGAM group. All the patients had been successfully engrafted. The trend towards lower acute GVHD II–IV rate had been more noticeably observed in the thymoglobulin group compared to the ATGAM group (28% vs. 70%; p=0.06). The risk of extensive chronic GVHD was also lower in the thymoglobulin group (28% vs. 78%; p=0.05). Overall survival for 1 year (71% vs. 47%; p=0.6) and 1-year TRM (15% vs. 48%; p=0.2) seemed to be better in patients who received thymoglobulin.

In conclusion, our study suggests that the use of thymoglobulin as a post–transplant prophylaxis could be associated with lower acute and/or chronic GVHD rates as well as with better outcomes in recipients of allo-SCT from mismatched unrelated donors as compared to ATGAM.

Keywords

GVHD, thymoglobulin, ATGAM, allo-SCT