Treatment of adults with acute lymphoblastic leukaemia in first bone marrow relapse: results of the ALL R-87 protocol

Sixty-one adults aged <55 years with acute lymphoblastic leukaemia (ALL) in first bone marrow relapse were enrolled in an Italian cooperative study (ALL R-87 protocol) from 12 GIMEMA Institutions. The treatment programme consisted of: (1) an induction phase with intermediate-dose cytarabine (IDARA-C 1 g/m², 6 h daily infusion ×6 d) plus idarubicin (IDA; 5 mg/m²/d × 6 d) and prednisone (40 mg/m²/d × 21 d), (2) a consolidation phase followed by (3) bone marrow transplant (BMT). Median first complete remission (CR) duration was 8.5 months (range 1–54 months). 34/61 patients achieved CR (56%); 24 (39%) failed to respond and three (5%) died during induction. Most responders (24 patients) could not enter the BMT programme; 15 relapsed early (median time to relapse 2 months); nine were withdrawn due to toxicity and one died in CR of infection. Nine of the 34 CRs underwent BMT (five autologous and four allogeneic). Three of the four allotransplanted patients are alive in continuous CR at 22, 43 and 63 months; only one of the five who underwent an autologous BMT is alive in CR at 46 months. The estimated disease-free survival (DFS ± SE) at 36 months was 0.16 ± 0.08 for all responders. Univariate analysis showed that previous therapy was the only prognostic factor influencing DFS. The estimated probabilities of event-free survival (EFS ± SE) and survival ± SE at 37 months were 0.09 ± 0.04 and 0.10 ± 0.04, respectively. The EFS was significantly better in patients with a preceding CR >24 months, compared to those with a shorter first remission. Our results confirm the tolerance and efficacy of IDARA-C plus IDA in inducing CR in poor-risk adult ALL. Even though the number of transplanted patients was small, allogeneic BMT seems to give a real opportunity of cure in this category of patients.     

Treatment of primary refractory and relapsed acute lymphoblastic leukaemia in children and adults: the GIMEMA/AIEOP* experience

One hundred and forty-seven patients aged <55 years with advanced acute lymphoblastic leukaemia (ALL) were enrolled in an Italian cooperative study (ALL R-87), This protocol consists of an induction phase with idarubicin (IDA) plus intermediate-dose cytarabine (IDARA-C), followed by a consolidation phase and bone marrow transplant (BMT). Complete remission (CR) was achieved in 97/147 patients (66%) with a CR rate of 77% in children versus 51% in adults ( P <0·01), 48 responders (50%) underwent BMT.
Probability of event-free survival (EFS ± SE) was 10·2±3·1% at 56 months. EFS was 14·3±4·51% at 56 months for children versus 3·8±3·41% at 37 months for adults ( P <0·0001). Among patients treated in first relapse, EFS was 14·2±7·79% for patients with CR >18 months versus 6·6±3·17% for those with CR <18 months ( P <0·0001).
Projected disease-free survival (DFS ±SE) was 15·4±4·61% at 55 months for all responders and 43·3±14·34% at 52 months for allografted patients. Projected overall probability of survival ±SE for all patients was 18·8±4·13% at 56 months.
This study confirms the efficacy of IDA plus IDARA-C in poor-risk ALL patients. A more intensive post-remission therapy or alternative approach must be designed to improve long-term results.     

Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children's Oncology Group

While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves relapse ALL response rates. This phase 2 Children's Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates (CR2). Evaluable patients (n = 135, 103 B-ALL, 22 T-ALL, 10 T-lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR2 rates were 68 ± 5% for precursor B-ALL patients (<21 years of age), 63 ± 7% for very early relapse (<18 months from diagnosis) and 72 ± 6% for early relapse (18–36 months from diagnosis). Relapsed T-ALL patients had an encouraging CR2 rate of 68 ± 10%. End of induction minimal residual disease (MRD) significantly predicted survival. MRD negative (MRDneg; MRD <0·01%) rates increased from 29% (post-cycle 1) to 64% following cycle 3. Very early relapse, end-of-induction MRDneg precursor B-ALL patients had 70 ± 14% 3-year event-free (EFS) and overall survival (OS) rates, vs. 3-year EFS/OS of 0–3% (P = 0·0001) for MRDpos (MRD ≥0·01) patients. Early relapse patients had similar outcomes (MRDneg 3-year EFS/OS 58–65% vs. MRDpos 10–19%, EFS P = 0·0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T-cell ALL, is worthy of further investigation. This study is registered at http://www.clinical.trials.gov as NCT00873093.     

Outcomes of treatment for relapsed acute lymphoblastic leukaemia in children with Down syndrome

Children with Down syndrome (DS) have a greater risk for developing both acute lymphoblastic leukaemia (ALL) and significant adverse effects of chemotherapy. We investigated their outcome with, and tolerance of, treatment protocols for relapsed ALL optimized in the paediatric population without DS. Probability of survival and causes of treatment failure were determined for 49 children with DS and a matched cohort of 98 children without DS among 2160 children treated for relapsed ALL in clinical trials conducted by the Berlin‐Frankfurt‐Münster ALL Relapse Study Group between 1983 and 2012. Despite more favourable ALL relapse characteristics, children with DS experienced lower event‐free (EFS) and overall survival (OS) than the control group without DS (EFS 17 ± 08% vs. non‐DS 41 ± 06%, P = 0·006; OS 17 ± 09% vs. non‐DS 51 ± 06%, P < 0·001). Children with DS developed more frequently fatal complications of treatment (34 ± 07% vs. non‐DS 10 ± 04%, P < 0·001). During the last decade, EFS and OS were no longer significantly different in children with and without DS (EFS 31 ± 09% vs. 36 ± 09%, P = 0·399; OS 31 ± 12% vs. 53 ± 09%, P = 0·151). DS proved an independent prognostic factor of outcome after ALL relapse. Induction deaths and treatment‐related mortality but not subsequent relapse were the main barrier to successful outcomes of relapse therapy in children with DS.     

Effect of arsenic trioxide on the treatment of children with newly diagnosed acute promyelocytic leukemia in China

To explore the efficacy of treatment for childhood acute promyelocytic leukemia (APL) with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (As₂O₃) for remission induction, we reviewed the clinical course and outcome of 37 children with APL from January 1999 to December 2003. Among the 37 children (≤14 years) with newly diagnosed APL, we applied treatments that consisted of ATRA alone or in combination with As₂O₃ in induction followed by consolidation and maintenance treatment. Overall, 35 (94.6%) of 37 children achieved complete remission (CR). Two patients died of intracerebral hemorrhage on days 1 and 2. The 5-year estimates of event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) rates for the 37 patients were 79.2, 83.7, and 91.5%, respectively. There were 27 patients with white blood cell (WBC) count lower than 10 × 10⁹/L. In 27 patients with a WBC count <10 × 10⁹/L, 17 patients (group-I) were treated with ATRA alone and 10 patients (group-II) were treated with ATRA which was switched to As₂O₃ due to the side effects of ATRA. Although the 5-year estimate of DFS between group-I and group-II showed no significant difference (P = 0.108), the DFS rate improved by 25% in group-II. Our results suggest that the combination of As₂O₃ and ATRA might decrease the relapse rate compared with ATRA alone in induction therapy for childhood APL, at least in those with a WBC count less than 10 × 10⁹/L.     

Pre‐ and post‐transplant minimal residual disease predicts relapse occurrence in children with acute lymphoblastic leukaemia

Relapse remains the leading cause of treatment failure in children with acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem cell transplantation (HSCT). We retrospectively investigated the prognostic role of minimal residual disease (MRD) before and after HSCT in 119 children transplanted in complete remission (CR). MRD was measured by polymerase chain reaction in bone marrow samples collected pre‐HSCT and during the first and third trimesters after HSCT (post‐HSCT1 and post‐HSCT3). The overall event‐free survival (EFS) was 50%. The cumulative incidence of relapse and non‐relapse mortality was 41% and 9%. Any degree of detectable pre‐HSCT MRD was associated with poor outcome: EFS was 39% and 18% in patients with MRD positivity <1 × 10⁻³ and ≥1 × 10⁻³, respectively, versus 73% in MRD‐negative patients (P < 0·001). This effect was maintained in different disease remissions, but low‐level MRD had a very strong negative impact only in patients transplanted in second or further CR. Also, MRD after HSCT enabled patients to be stratified, with increasing MRD between post‐HSCT1 and post‐HSCT3 clearly defining cohorts with a different outcome. MRD is an important prognostic factor both before and after transplantation. Given that MRD persistence after HSCT is associated with dismal outcome, these patients could benefit from early discontinuation of immunosuppression, or pre‐emptive immuno‐therapy.     

Minimal residual disease assessed by multi‐parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia

The prognostic value of minimal residual disease (MRD) assessed by multi‐parameter flow cytometry (MFC) was investigated among 340 adult patients with B‐cell acute lymphoblastic leukaemia (B‐ALL) treated between 2004 and 2014 using regimens including the hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) backbone. Among them, 323 (95%) achieved complete remission (CR) and were included in this study. Median age was 52 years (range, 15–84). Median white blood cell count (WBC) was 9·35 × 10⁹/l (range, 0·4–658·1 ×1 0⁹/l). MRD by MFC was initially assessed with a sensitivity of 0·01%, using a 15‐marker, 4‐colour panel and subsequently a 6‐colour panel on bone marrow specimens obtained at CR achievement and at approximately 3 month intervals thereafter. MRD negative status at CR was associated with improved disease‐free survival (DFS) and overall survival (OS) (P = 0·004 and P = 0·03, respectively). Similarly, achieving MRD negative status at approximately 3 and 6 months was associated with improved DFS (P = 0·004 and P < 0·0001, respectively) and OS (P = 0·004 and P < 0·0001, respectively). Multivariate analysis including age, WBC at presentation, cytogenetics (standard versus high risk) and MRD status at CR, 3 and 6 months, indicated that MRD negative status at CR was an independent predictor of DFS (P < 0·05). Achievement of an MRD negative state assessed by MFC is an important predictor of DFS and OS in adult patients with ALL.     

Absolute lymphocyte count at day 28 independently predicts event-free and overall survival in adults with newly diagnosed acute lymphoblastic leukemia

We investigated the prognostic impact of absolute lymphocyte count (ALC) following induction chemotherapy in newly diagnosed adult acute lymphoblastic leukemia (ALL). Patients with ALC ≥350 cells/μL at day 28 had a median overall survival (OS) of 47.4 months when compared with 17.6 months for those with an ALC <350 cells/μL (HR = 1.98, P = 0.007). Among patients who achieved a complete remission, median event‐free survival (EFS) for those with ALC ≥350 cells/μL on day 28 was 42.1 months when compared with 13.9 months in those with ALC <350 cells/μL (HR = 2.08, P = 0.006). In multivariable analysis, the ALC on day 28 (<350 cells/μL vs. ≥350 cells/μL, P ≤ .0004 for OS and EFS) along with WBC at diagnosis (≤6.0 or >30.0 K/μL vs. >6.0–30.0 K/μL, P ≤ 0.002 for OS and EFS) and cytogenetics (abnormal vs. normal, P = 0.002 for OS and P = 0.02 for EFS) were independent prognostic factors of both OS and EFS. Combining these three factors segregates patients in three well‐defined risk groups. These data suggest that ALC can be used in combination with other prognostic features to better predict outcome and that targeting the immune system to improve ALC may be a worthwhile strategy in ALL. Am. J.Hematol. © 2012 Wiley Periodicals, Inc.     

Allogeneic bone marrow transplantation versus chemotherapy in high-risk childhood acute lymphoblastic leukaemia in first remission

We compared the outcome of children with high-risk acute lymphoblastic leukaemia (HR-ALL) in first complete remission (first CR) treated with chemotherapy (CHEMO) or with allogeneic bone marrow transplantation (BMT) in a multicentre study.   All children treated by the Italian Paediatric Haematology Oncology Association for HR-ALL in first CR between 1986 and 1994 were eligible for the study. 30 children were given BMT at a median of 4 months from first CR, with preparative regimens including total-body irradiation ( n  =25/30). 130 matched controls for BMT patients were identified among 397 HR-ALL CHEMO patients. Matching on main prognostic factors and duration of first CR was adopted to control the selection and time-to-transplant biases. The comparative analysis was based on the results of a stratified Cox model. The estimated hazard ratios of BMT versus CHEMO at 6 months, 1 year and 2 years after CR were 1.38 (CI 0.59–3.24), 0.69 (CI 0.27–1.77) and 0.35 (CI 0.06–1{\raise 5mu ..91), with an overall non-significant difference between the two groups ( P  = 0.34). With a median follow-up of 4 years, the disease-free survival was 58.5% (SE 9.3) in the BMT group and 47.7% (SE 4.8) in the CHEMO group, at 4 years from CR. Non-leukaemic death occurred in 4% of CHEMO and 10% of BMT patients. In the BMT group the estimated cumulative incidence of relapse at 1.5 years from CR was 31.5% (SE 8.8) and did not change thereafter, whereas in the CHEMO group the corresponding figure was 29.2% (SE 4.1) and the incidence continued to increase thereafter (48.2% (SE 4.8) at 4 years from CR).   The results of this study suggest that, with respect to the CHEMO group, the higher risk of early failure in the BMT group is outweighed by the lower risk of relapse after 1 year. Results prompt the need for a prospective study, in order to demonstrate the likely advantage of BMT in HR childhood ALL in first CR.     

Treatment of acute promyelocytic leukemia with PETHEMA LPA 99 protocol: a Tunisian single center experience

Abstract

Acute promyelocytic leukemia (APL) has now become the most curable of all subtypes of acute myeloid leukemia. A cure rate of 75–80% can be anticipated with a combination of all-trans retinoic acid (ATRA) and anthracyclines. In Tunisia, the ATRA era began in 1998 with the use, consecutively, of two regimens of a combination of ATRA with anthracycline and cytarabine (APL93), and without cytarabine (LPA99). From 2004, 39 patients with confirmed APL either by t(15;17) or PML/RARA were treated by the PETHEMA LPA 99 trial. The rationale of this protocol by avoiding cytarabine is to reduce death in complete remission (CR) without increasing the incidence of relapse. Thirty-three patients achieved CR (84·6%). The remaining six patients were considered as failure due to early death: three caused by differentiation syndrome (DS) and three died from central nervous system hemorrhage. Baseline blood cell count (WBC) >10 × 10⁹/l (P=0·26) and creatinine >1·4 mg/dl (P=0·42) were not predictive of mortality. DS was observed in 11 patients (30·5%) with a median onset time of 12 days (range: 3–23 days) and median WBC of 29 × 10⁹/L (range: 1·2 × 10⁹–82·7 × 10⁹/l). DS was severe in seven cases, moderate in four, and fatal in three cases. Body mass index ≥30 (P=0·044) and baseline WBC ≥20 × 10⁹/l (P=0·025) are independent predictors of DS. The median follow-up of this study is 36 months. Thirty patients are alive in continuous complete remission; two patients died in CR from septic shock and secondary myelodysplastic syndrome respectively; one patient died 47 months after achieving two relapses. Event free survival from diagnosis was 80% and overall survival was 82%. Our results are quite acceptable and can be improved by reducing mortality rate.     

Acute leukaemias of ambiguous lineage in children: characterization,prognosis and therapy recommendations

Acute leukaemias of ambiguous lineage (ALAL) represent a rare type of leukaemia, expressing both myeloid and lymphoid markers. This study retrospectively analyzed data from 92 children (biphenotypic n = 78, bilineal n = 6, lineage switch n = 8) with ALAL registered in the Berlin‐Frankfürt‐Münster (BFM) acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) studies between 1998 and 2006 (2·4% of all cases with acute leukaemia). Our cohort of ALAL patients was characterized by comparatively high median age (8·9 years), high median white blood cell count (14·9 × 10⁹/l), as well as frequent hyperleucocytosis (18·5%) and central nervous system involvement (24·1%). The most frequent cytogenetic abnormalities were ETV6/RUNX1 fusion (16%) and trisomy 8 (14·6%). Complete remission rate was significantly lower than in ALL‐BFM patients (91·8% vs. 99·1%, P < 0·001), but comparable to AML‐BFM patients (87·9%). Event‐free survival (EFS) and overall survival (OS) of ALAL patients were low, at 62 ± 5%. 5‐year probability of EFS was significantly worse than in ALL patients (80 ± 1%, P < 0·001), but better than for AML patients (49 ± 2%, P = 0·027). Our data suggest that an intensive therapy regimen including stem cell transplantation may be favourable for bilineal or lineage switch cases, whereas patients with ETV6/RUNX1 fusion, lymphoid morphology and patients with expression of cyCD22 and cyCD79a should be treated with an ALL‐directed therapy.     

Minimal residual disease before and after transplantation for childhood acute lymphoblastic leukaemia: is there any room for intervention?

Eighty‐two children and adolescents who underwent allogeneic transplantation for acute lymphoblastic leukaemia in remission (period 2001–2011, median follow‐up 4·9 years) had been assessed for minimal residual disease (MRD) by real‐time quantitative polymerase chain reaction before and at 1, 3, 6, 9 and 12 months after transplantation. Five‐year event‐free survival (EFS) and cumulative incidence of relapse were 77·7% [standard error (SE) 5·7] and 11·4% (SE 4·4), respectively, for patients with pre‐transplant MRD <1 × 10^?4 (68%), versus 30·8% (SE 9·1; P < 0·001) and 61·5% (SE 9·5; P < 0·001), respectively, for those with MRD ≥1 × 10^?4 (32%). Pre‐transplant MRD ≥1 × 10^?4 was associated with a 9·2‐fold risk of relapse [95% confidence interval (CI) 3·54–23·88; P < 0·001] compared with patients with MRD <1 × 10^?4. Patients who received additional chemotherapy pre‐transplant to reduce MRD had a fivefold reduction of risk of failure (hazard ratio 0·19, CI 0·05–0·70, P = 0·01). Patients who experienced MRD positivity post‐transplant did not necessarily relapse (5‐year EFS 40·3%, SE 9·3), but had a 2·5‐fold risk of failure (CI 1·05–5·75; P = 0·04) if any MRD was detected in the first 100 d, which increased to 7·8‐fold (CI 2·2–27·78; P = 0·002) if detected after 6 months. Anticipated immunosuppression‐tapering according to MRD may have improved outcome, nevertheless all patients with post‐transplant MRD ≥1 × 10^?3 ultimately relapsed, regardless of immunosuppression discontinuation or donor‐lymphocyte‐infusion. In conclusion, MRD before transplantation had the strongest impact on relapse and MRD positivity after transplantation, mostly if detected early and at low levels, did not necessarily imply relapse. Additional intensified chemotherapy and modulation of immunosuppression may reduce relapse risk and improve ultimate outcome.     

Factors affecting the outcome of stem cell transplantation from unrelated donors for childhood acute lymphoblastic leukemia in third remission

Between July 1990 and March 2002, 35 consecutive children with ALL in third complete remission (CR3) underwent stem cell transplantation (SCT) from unrelated donors (UD). All patients received CAMPATH-1M 5-20 mg daily for 5 days. Grafts were T-cell depleted in 30 patients, 29 by CAMPATH antibodies and one by CD34 selection. Median follow-up was 3.8 years (0.3-9.3). Event-free survival (EFS) at 3 years was 35% (SE 8%); relapse rate and transplant-related mortality (TRM) at 3 years was 42 and 23%. Short first complete remission (CR1) <2.5 years was associated with lower EFS (P=0.001), higher TRM (P=0.019) and higher relapse rate (P=0.023). Short second complete remission (CR2) <2.5 years was associated with lower EFS (P=0.003) and higher TRM (0.009). Higher relapse rate and lower EFS were associated with isolated first extramedullary relapse (P=0.019, 0.012). There was no significant difference in outcome between mismatched unrelated donor stem cell transplantation (MMUD-SCT) and matched unrelated donor stem cell transplantation (UD-SCT). We conclude that UD-SCT is an effective treatment of ALL in CR3. The outcome remains limited by TRM and a high relapse rate. Short duration of CR1 and of CR2 and extramedullary site at first relapse are particularly adverse. MMUD should also be considered in high-risk patients, since the outcome of MMUD appears similar to MUD.     

Association between leukocyte count and the presence and extent of coronary atherosclerosis as determined by coronary arteriography

Angiographic evidence of coronary artery disease (CAD) was correlated with leukocyte count (WBC), red cell count (RBC), cigarette smoking, age, sex, and cholesterol and triglyceride concentrations in 573 patients who underwent coronary arteriography and who did not have evidence of infection or recent myocardial infarction. Smokers had a higher WBC (7,449 ± 1,964leukocytes/mm³ vs 6,533 ± 1,557, p = 0.0001) and RBC (4.921 × 10⁶ ± 0.491 × 10⁶ erythrocytes/mm³ vs 4.753 × 10⁶ ± 0.480 × 10⁶ p = 0.0001) than nonsmokers. Patients with CAD had a higher WBC (7,280 ± 1,926 vs 6,664 ± 1,700, p = 0.0005) and RBC (4.903 × 10⁶ ± 0.488 vs 4.777 × 10⁶ ± 0.485 × 10⁶, p = 0.0062) than those with normal coronary arteriograms. A positive correlation between WBC and the severity of CAD (sum of arterial diameter narrowing) was noted (r = 0.16, p = 0.0001). Multiple regression showed an independent contribution of WBC in predicting severity of CAD (F = 9.26, p = 0.0025), after accounting for the effects of age, sex, serum cholesterol and triglyceride levels. When smoking was entered into the equation, the contribution of WBC in predicting the severity of angiographic CAD became weaker (F = 4.46, p = 0.035). Similar relations were seen when only smokers were analyzed and when patients with history of remote myocardial infarction were excluded. In nonsmokers these associations became either insignificant or much weaker. Thus, the relation of WBC, and RBC with CAD is mainly due to the elevation of WBC and RBC and the increase of CAD risk induced by cigarette smoking.     

Early response to induction is predictive of survival in childhood Philadelphia chromosome positive acute lymphoblastic leukaemia: results of the Medical Research Council ALL 97 trial

We report on the outcome of children with Philadelphia positive acute lymphoblastic leukaemia (Ph+ ALL) treated on the UK Medical Research Council (MRC) trial for childhood ALL, MRC ALL 97, between January 1997 and June 2002. Forty-two (2.3%) patients were Ph+. Nineteen (45%) had <25% blasts in bone marrow (BM) within the first 2 weeks of treatment and were defined as a good response group (GRG), the others as a poor response group (PRG). Thirty-six (86%) achieved first complete remission (CR1) at the end of induction, of which 28 underwent BM transplantation (BMT). The median follow-up was 42 months (range, 21-84). The 3-year event-free survival (EFS; 52%, 95% CI, 36-66%) was a considerable improvement on the previous MRC UKALL XI trial (27%). EFS for the GRG and PRG were 68% (43-84%) and 39% (18-59%), respectively (P = 0.03); presenting white cell count <50 x 10(9)/l (P = 0.02) was predictive for overall survival. Changes in the MRC ALL97 trial within the study period resulted in some Ph+ ALL receiving daunorubicin and either prednisolone or dexamethasone during induction. Though the use of daunorubicin during induction was not a prospective study question, EFS was significantly better for those whose induction included this drug (P = 0.02). Steroid randomization was not stratified for Ph+ ALL patients and was not predictive for EFS. BMT in CR1 appeared to reduce the risk of a subsequent BM relapse. These results show significant improvement on previous MRC trials; future therapeutic strategies should include early intensive therapy and BMT in CR1.     

Clinical characteristics and outcome of childhood acute promyelocitic leukemia (APL) in Saudi Arabia: a multicenter SAPHOS leukemia group study

Background: Acute promyelocytic leukemia (APL) is a rare form of acute myelogenous leukemia (AML). Survival rates exceed 80% in developed countries. Successful treatments rely on all-trans retinoic acid with anthracycline-based chemotherapy. Availability of modern care and public knowledge play important roles in pediatric APL survival.

Method: A cytogenetic diagnosis of APL was confirmed in 30 (14.5%) out of 207 children consecutively diagnosed with de novo AML between January 2005 and December 2012 at nine cancer care centers in Saudi Arabia. Patients were treated based on the standard protocol used by the center following the PETHEMA or the C9710 treatment protocols. We modeled 5-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) vs. treatment and potential covariates of age at diagnosis, involvement of central nervous system (CNS), and white blood cell (WBC) levels.

Results: The median age was 10.4 years with a male:female ratio of 1.9. WBC was 10?×?10⁹/l or greater in 57% and CNS involvement was confirmed in 13%. OS, EFS, and CIR were 74?±?12%, 55?±?19%, and, 36?±?17% respectively. No significant difference was found by treatment protocol. WBC levels were significantly prognostic for all negative events, but treatment with C9710 significantly ameliorated negative WBC effects. Overall outcomes were comparable to those reported in developed countries.

Conclusions: Access to modern care is likely to be a critical factor in successful and comparable outcomes of childhood APL across the globe. In the present study, utilizing a cytarabine-containing protocol improved outcome of high-risk pediatric patients with APL.     

Significance of recurrence of minimal residual disease detected by multi‐parameter flow cytometry in patients with acute lymphoblastic leukemia in morphological remission

We sought to determine the significance of minimal residual disease (MRD) relapse in patients with ALL after achieving MRD negative status following induction and consolidation therapy. Between January 2003 and September 2014, 647 newly diagnosed patients were treated [HyperCVAD‐based (n = 531); Augmented BFM (n = 116)]. Six hundred and one (93%) achieved complete remission (CR), and 546 (91%) became MRD negative. Fifty‐five patients [HyperCVAD‐based (n = 49); Augmented BFM (n = 6)] developed recurrence of MRD while still in morphological CR and are the subjects of this study. MRD was assessed by 6‐color (4‐color prior to 2009) multi‐parameter flow cytometry (MFC) at CR and multiple time points thereafter. Their median age was 44 years (range, 18–72 years), median WBC at initial presentation was 7.3 K/µL^?1 (range, 0.6–303.8 K/µL^?1) and median bone marrow blast percentage 88% (range, 26–98%). The median time to MRD relapse was 14 months (range 3–58 months). Forty‐four (80%) patients subsequently developed morphological relapse after median of 3 months (range, <1–33 months) from detection of MRD recurrence. Treatments received after MRD positivity and prior to morphological relapse: 16 continued maintenance chemotherapy; 15 received late intensification; 9 allogeneic stem cell transplant, 9 changed chemotherapy, 6 no further therapy. Only six remain alive and in CR1 and nine are alive after morphological relapse. MRD relapse detected by MFC at any time after achieving CR is associated with a high risk for morphological relapse. SCT can result in long‐term remission in some patients. Prospective studies of long‐term MRD assessments, together with less toxic treatment strategies to eradicate MRD, are warranted.     

Allogeneic bone marrow transplantation in second remission of childhood acute lymphoblastic leukemia: a population-based case control study from the Nordic countries

This study compares allogeneic BMT with conventional chemotherapy for childhood ALL in second remission. Seventy-five children were transplanted between July 1981 and December 1995. For each patient two control patients matching the following criteria were selected from the Nordic database of ALL: (1) time of diagnosis, (2) T vs. non-T ALL, (3) site of relapse, (4) initial risk group, (5) sex and (6) relapse < or > or =6 months after cessation of therapy. The minimal time of follow-up was 24 months. Mortality rate in CR2, leukemic relapse rate and the proportion in continued second remission were 16/75 (21%), 22/75 (29%) and 37/75 (50%), respectively. P2.-EFS for the BMT group was significantly better than that for the control group (0.40 vs. 0.23, P = 0.02). Children transplanted for bone marrow relapses in particular had a higher P2.-EFS (0.35 vs. 0.15 for the control group, P<0.01). Also, children grafted for early BM relapses had a higher P2.-EFS (0.32 vs. 0.11 for the control group P = 0.01). The outcome was similar when children were transplanted after early or late relapse. Also, there was no difference in outcome between the BMT and the chemotherapy group for children with late relapses. We conclude that allogeneic BMT with an HLA-identical sibling donor or other family donor should be performed in children relapsing in bone marrow during therapy or within 6 months of discontinuing therapy.     

Mycophenolate mofetil: A possible therapeutic agent for children with juvenile dermatomyositis

Objective

To determine if mycophenolate mofetil (MMF) diminishes skin and muscle disease activity in children with juvenile dermatomyositis (DM), thereby permitting a decrease in corticosteroid dose.

Methods

A retrospective data review for 50 children with juvenile DM (mean ± SD age 12.2 ± 5.0 years) who had received MMF for 12 months identified the following characteristics: 38 (76%) were girls, 39 (78%) were white, 10 (20%) were Hispanic, and 1 (2%) was African American. The MMF dose and frequency, type of infection, white blood cell (WBC) count, corticosteroid dose, and the validated disease activity score (DAS) subscores for skin (DAS‐S) and muscle (DAS‐M) were obtained.

Results

Twelve months after the start of MMF, the mean ± SD DAS‐S decreased from 5.24 ± 0.29 to 3.72 ± 0.29 (P = 0.001), and the mean ± SD DAS‐M decreased from 2.44 ± 0.39 to 1.17 ± 0.28 (P = 0.002). The mean ± SD prednisone dosage decreased from 0.39 ± 0.06 to 0.23 ± 0.02 mg/kg/day (P = 0.0001), with resumption of linear growth (P = 0.008). The WBC/lymphocyte count was unchanged over the 12 months on MMF. The infection rate was assessed in a subset of 26 children with juvenile DM who were observed for 12 months before the start of MMF and then compared with the ensuing 12 months of MMF therapy. There was no significant difference between the pretreatment period and the first 6 months of MMF therapy (P = 0.44), but the infection rate decreased in months 7–12 (P = 0.001).

Conclusion

MMF appears to be worthy of consideration as an additional therapeutic modality for treatment of children with juvenile DM. These data suggest that the use of MMF decreases skin and muscle disease activity and is steroid sparing. MMF appears to be well tolerated, but patients should be monitored for infection.