Managing Suspected APL
Frequent abrupt onset and risk of severe hemorrhagic events means that immediate institution of ATRA and/or ATO treatment and supportive therapies are critical for the correct management of APL, and especially to avoid fatal outcomes. Start these measures upon clinical suspicion of APL, without waiting for genetic confirmation of an APL diagnosis.
Suspicion of APL generally arises from characteristic bone marrow morphology with infiltrate of abnormal hypergranular promyelocytes. The morphologic hypogranular variant, M3v, identified in around 20% of cases, is challenging as it resembles other AML subsets (M5 or M1 types).
Antigen expression is distinctive but not diagnostic of APL. Flow cytometry indicates generally:
- Strong positivity for CD33, CD13 and CD117
- Infrequent expression of HLA-DR and CD34
- No expression of CD11a, CD11b and CD14.
Although not diagnostic, this antigenic profile may alert to a possible diagnosis of APL. Follow morphologic of flow-cytometry suspicion by immediate institution of ATRA and/or ATO therapy, and subsequent aggressive replacement of platelets, fresh-frozen plasma (or cryoprecipitates) to counteract the ongoing coagulopathy without waiting for genetic confirmation.
Institute transfusion support to maintain the fibrinogen concentration above 100‑150 mg/dL and platelet count above 30‑50×109/L. During induction, avoid invasive procedures routinely done at presentation in other acute leukemias – like central line placement (peripherally inserted central catheter [PICC] line is acceptable) and lumbar puncture in the immediate setting – to avoid thrombo-hemorrhagic complications. Similarly, avoid leukapheresis in hyperleucocytic patients, even in those showing signs of leukostasis.
Search for the PML-RARA gene rearrangement and other possible translocations remains essential as the response to specific therapy depends on the presence and type of the genetic lesion. Experienced reference laboratories must be involved in this step e.g. Laboratory of Onco-hematology, Policlinico Tor Vergata, Rome, Italy.
Current methods for genetic confirmation of APL diagnosis include assays to identify PML‑RARA lesion at the DNA, RNA and chromosome level using FISH and reverse transcriptase (RT)-PCR, and indirect immunofluorescence tests to assess the nuclear distribution pattern of the PML protein.
- FISH analysis is preferred over karyotyping on G-banded metaphases because it does not require good quality metaphases and it overcomes the possible false negatives arising with conventional karyotype analysis in case of cryptic or complex rearrangements.
- RT-PCR is well-standardized and the only diagnostic assay also identifying the precise PML-RARA transcript isoform (long, short or variant) essential for subsequent molecular monitoring of minimal residual disease.
- Immunofluorescence analyses of nuclear distribution of PML protein are possible within 2 hours using bone marrow smears. The test distinguishes the characteristic PML/RARA “microspeckled” staining pattern from the so called “nuclear bodies” pattern characteristic of other leukemias and normal hematopoietic cells. This rapid and cheap assay is highly recommended in small laboratories not equipped and/or experienced for molecular testing.
| Current Recommendation |
|---|
| Low to intermediate–Risk Patients |
| Concomitant use of ATO and ATRA in low-intermediate risk patients >18 and in those patients who are not candidates to chemotherapy+ATRA |
| High-Risk Patients |
| Concomitant ATRA and anthracycline-based chemotherapy for high risk patients |
| Do not modify standard induction therapy based on the presence of leukemia cell characteristics that have variably been considered to predict a poorer prognosis (e.g. secondary chromosomal abnormalities, FLT3 mutations, CD56 expression, and BCR3 PML-RARA isoform) |
| Use ATRA plus chemotherapy as standard therapy in countries where pharmaceutical quality locally produced provide is the only affordable treatment approach |
| Continue treatment with ATRA and/or ATO until terminal differentiation of blasts and achievement of CR, which occurs in virtually all patients |
| Do not make therapeutic modifications on the basis of incomplete blast maturation (differentiation) by morphology or persistence of PML-RARA gene assessed by cytogenetics, or molecular biology |
| Abbreviations: ATO, arsenic trioxide; ATRA, all-trans retinoic acid; BCR3, short PML-RARA isoform; CR, complete hematological remission; FLT3, fms-like tyrosine kinase 3 (gene); PML-RARA, promyelocytic-retinoic acid alpha receptor (gene).
|
| Current Recommendation |
|---|
| Low to intermediate–Risk Patients |
| In patients with low-intermediate risk disease treated with ATRA-ATO, 4 consolidation cycles with ATO and 7 with ATRA are needed. |
| In patients with low-intermediate risk disease treated with ATRA and chemotherapy, 3 consolidation courses are recommended followed by maintenance therapy with low-dose chemotherapy and ATRA |
| High-risk Patients |
| For high-risk patients <60 years, include at least one cycle of intermediate- or high-dose cytarabine |
| Assess molecular remission in the bone marrow at completion of consolidation by RT‑PCR assay affording a sensitivity of ≥1 in 104 |
| Consider patients with confirmed molecular persistence for allogeneic HSCT |
| Consider patients with molecular persistence who are not candidates for allogeneic HSCT, for ATO or gemtuzumab ozogamicin therapy |
| Abbreviations: ATO, arsenic trioxide; ATRA, all-trans retinoic acid; HSTC, hematopoietic stem cell transplant; RT-PCR, reverse transcriptase-polymerase chain reaction; WBC, white blood cell. |
| Current Recommendation |
|---|
| Use maintenance therapy for patients who have received an induction and consolidation treatment regimen, for which maintenance has shown a clinical benefit |
| Early treatment intervention in patients with evidence of MRD gives a better outcome than treatment in full-blown relapse. Therefore, offer all patients MRD monitoring of bone marrow every 3 months for up to 3 years after completion of consolidation therapy. |
| Sample bone marrow (which has greater sensitivity for detection of MRD over blood) for MRD monitoring to guide therapy |
| For patients testing PCR-positive at any stage after completion of consolidation, repeat bone marrow sampling for MRD assessment within 2 weeks and send samples to the local laboratory, as well as to a reference laboratory for independent confirmation of molecular relapse |
| Consider CNS prophylaxis only for patients with hyperleukocytosis |
| Abbreviations: CNS, central nervous system; MRD, minimal residual disease; PCR, polymerase chain reaction.
|
Background to the Management of Newly Diagnosed Patients
The first prospective non-randomized trials using a chemotherapy-free approach were conducted in India [Mathews 2006] and Iran [Ghavamzadeh 2006] with ATO administered as single agent both for induction and consolidation therapy. The Indian study reported at a median of 25 months follow-up, 3-year estimates of event-free survival (EFS), disease-free survival (DFS) and overall survival (OS) of 74.87 ± 5.6, 87.21 ± 4.93, and 86.11 ± 4.08 %, respectively. The Iran study reported similar results with 2-year DFS and 3-year OS of 63.7% and 87.6%, respectively. Both studies showed significantly better outcomes for patients with low risk disease.
A pilot study with ATRA and ATO combined was conducted in the United States [Estey 2006]. Forty-four patients (25 low-risk and 19 high-risk) received induction therapy with ATRA and ATO (0.15 mg/kg daily, 10 days after starting ATRA) until achievement of complete remission, followed by four 28-day consolidation cycles with the same induction schedule. Fifteen of the high-risk patients additionally received a single dose of gemtuzumab ozogamicin (GO) 9 mg/m2 administered on Day 1; the 3 remaining high-risk patients received GO plus idarubicin 12 mg/m2 on Days 1 to 3, or idarubicin alone on Days 1 to 4). Overall CR rate was 89% (96% in low-risk and 79% in high-risk patients) and relapses were detected in 3 high-risk patients (after 9, 9 and 15 months, respectively), and none of the low-risk patients.
An update [Ravandi 2009] of Estey’s 2006 trial on an extended series of 82 patients treated with the same schedule with 17 patients receiving both ATRA and ATO on Day 1, confirmed at a median follow-up of 99 weeks, high CR rates (92%) and an estimated 3-year OS of 86%. Also using this schedule, the results were significantly better for low-risk patients.
The APL0406 randomized study conducted by Italian and German investigators [Lo-Coco 2013] directly compared the standard ATRA plus chemotherapy and the novel chemotherapy-free regimen as proposed by MDACC investigators. Concomitant ATO plus ATRA during induction therapy was followed by 4 consolidation cycles with intermittent ATO and ATRA, per Ravandi 2009. With a median follow-up of 34 months for eligible patients, this combination therapy was superior in terms of either EFS or OS to the standard ATRA and idarubicin (AIDA) (2-year EFS: 97% versus 86%, p=0.02; 2‑year OS: 99% versus 91%; p=0.02) and was associated with significantly less myelosuppression and infections.
Regarding other toxicities, more frequent hematologic and GI toxicity was reported in the chemotherapy arm, while liver enzymes elevation and episodes of QTc prolongation were more observed in patients receiving ATRA-ATO, however these side effects were reversible and managed with protocol recommended temporary drug discontinuation [Lo-Coco 2013]. Based on the results of this randomized trial, the updated US National Comprehensive Cancer Network (NCCN) guidelines included the ATRA-ATO combination as the favored option for front-line therapy of low and intermediate risk APL patients.
A 2016 update of Lo-Coco’s 2013 trial on an extended series of 276 patients with a median follow-up of 40 months, showed survival advantage for ATRA-ATO over ATRA-chemotherapy with significant increases over time for EFS (2-year EFS 98% versus 84.9%, P= 0.0002) and OS (2-year OS 99.1% versus 94.4%, P=0.01) [Platzbecker 2016]. In addition, while no significant difference in cumulative incidence of relapse (CIR) rate was observed between the two treatment arms in the initial series, a significantly lower CIR was detectable in the updated series in the ATRA-ATO group compared to the AIDA cohort (1.1% and 9.4%, respectively; p=0.005) [Platzbecker 2016].
The AML17 trial independently conducted in the UK by the National Cancer Research Institute (NCRI) cooperative group confirmed the benefit of the ATRA-ATO chemotherapy-free over the standard ATRA-chemotherapy approach [Burnett 2015]. In this study, a widely used ATRA and chemotherapy (AIDA protocol) approach and an ATRA-ATO combination with a different schedule for ATO were compared. ATO was given at 0.3 mg/kg on Days 1-5 of each course and then in Weeks 2-8 of course 1 and Weeks 2-4 of courses 2-5 at 0.25 mg/kg twice weekly. Fifty-seven patients with high-risk disease were included with provision to receive 1 or 2 infusions of GO 6 mg/m2) during the first 4 days of induction therapy. At a median follow-up of 32.5 months, significant benefit was evident for ATRA-ATO compared to AIDA in terms of 4-year EFS (91% versus 70%; p=0.002), 4-year molecular recurrence-free survival (98% versus 70%; p=<0.0001) 4-year cumulative incidence of molecular relapse (1% versus 18%; p=0.0007). OS was comparable between the ATRA-ATO and AIDA groups (93% versus 89%) [Burnett 2015].
In summary, the results of the two randomized studies conducted by large cooperative groups strongly support ATRA-ATO as the new standard of care at least in low-risk patients with APL. Regarding high-risk disease, the low number of patients included in the UK NCRI study probably leaves open the issue of the most appropriate regimen. In this context, a randomized study comparing AIDA and ATRA-ATO plus minimal chemotherapy in high risk APL is ongoing (EudraCT number 2015-001151-68: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-001151-68/DE)
Managing Relapsed or Refractory Patients
Molecular assessment, using RT-PCR, at the conclusion of consolidation therapy and beyond, is an appropriate time point at which to determine the patient’s molecular status in terms of remission or relapse and to assess the risk of relapse. Hematological remission requires molecular confirmation. Achievement of molecular remission is a major treatment objective to meet in APL. Some patients may have recurrent or persistent disease at the molecular level and will invariably relapse without additional treatment. The central nervous system (CNS) is the commonest site of extramedullary disease in APL and at least 10% of hematologic relapses are accompanied by CNS involvement. For patients experiencing relapse, follow the management recommendations in Table 4 (management of relapse).
| Current Recommendation |
|---|
| For patients with confirmed molecular relapse (defined as 2 successive PCR-positive assays, with stable or rising PML-RARA transcript levels detected in independent samples taken at least 2 weeks apart-may be useful in case of doubts to send to reference laboratories), start pre-emptive therapy promptly to prevent frank relapse |
| Regard ATO-based regimens as the first option. Note that ATRA in combination with chemotherapy may be used as salvage therapy |
| Intensify HSCT or chemotherapy, if possible, to patients achieving second CR |
| Institute allogeneic HSCT for patients failing to achieve a second molecular remission |
| Consider autologous HSCT for patients without detectable MRD in the marrow and with an adequate PCR negative harvest |
| For patients in whom HSCT is not feasible, consider repeat cycles of ATO with or without ATRA with or without chemotherapy |
| For patients with CNS relapse, give induction treatment of weekly triple ITT with methotrexate, hydrocortisone, and cytarabine until complete clearance of blasts in the cerebrospinal fluid, followed by 6 to 10 more spaced out ITT treatments as consolidation. Also give systemic treatment. |
| Abbreviations: ATO, arsenic trioxide; ATRA, all-trans retinoic acid; CNS, central nervous system; CR, complete hematological remission; HSTC, hematopoietic stem cell transplant; ITT, intrathecal therapy; MRD, minimal residual disease; PCR, polymerase chain reaction; PML-RARA, promyelocytic-retinoic acid alpha receptor (gene). |
Background to the Management of Relapsed or Refractory APL
With modern therapy, relapsed/refractory APL is rare, as 90% of patients achieve CR after initial therapy and 80% are cured and there are even fewer relapses in the context of ATO-ATRA chemotherapy-free protocols.
Failure to achieve remission after ATRA-based induction therapy is exceedingly rare, and largely restricted to patients with rare ATRA-resistant variants, such as PLZF-RARA positive APL. Resistance to ATO was described in the relapsed setting and a probable explanation may be found by the use of direct sequencing, 9 of whom harbored PML mutations, and 7 of these simultaneously harbored RARA mutations [Zhu 2014].
Relapse occurs in 5–20% of patients treated with ATRA+chemotherapy approach, with <3% of patients with low-risk disease relapsing, but closer to 20% relapse rate in some series of high-risk patients, although this rate appears to be lower at around 10–12% in contemporary series [Sanz 2010; Iland 2012]. In APL cases treated with ATRA+ATO, relapse occur at even lower rates with 1-2% reported in recent randomized trials. Relapse at extramedullary sites is an increasingly recognized problem in 3–5% of patients [Specchia 2001].
Therapeutic options for relapsed/refractory APL have included ATO, thought to be the single most active agent in APL, [Niu 1999]. Further treatment options for relapsed disease include combinations of ATO with chemotherapy such as anthracyclines and anti-CD33 humanized antibodies.
As ATO is now a licensed front-line therapeutic strategy, the response to ATO in relapse for patients previously exposed to ATO will emerge as an issue of importance for small and ever decreasing numbers of patients.
A retrospective study examined 64 consecutive first-relapsed APL patients receiving salvage therapy with ATO and chemotherapy, 52 of whom had a hematologic relapse. Of patients with hematologic relapse, 20 had relapsed after previous ATO therapy and 32 did not receive prior ATO therapy. There was no statistically significant difference between a second CR (CR2) rate (80% versus 93.8%, P = 0.189) or 4-year OS rate (62.4% versus 71.2%, P = 0.816), but there was a statistically significant difference between relapse rate (68.8% versus 33.3%, P = 0.03) and 4-year relapse-free survival rate (29.8% versus 66.2%, P = 0.023) [Lou 2014]. This study was limited by its retrospective design and small number of patients. Larger prospective studies may help elucidate the utility of rechallenge with ATO in previously exposed patients.
Once a patient has achieved CR2, hematopoietic stem cell transplantation (HSCT) can be considered. Autologous and allogeneic transplants are associated with durable remission and prolonged survival [Pemmaraju 2013], although autologous HSCT yields the best outcomes in all comparative studies.
A phase 2 study of 35 patients evaluating the efficacy and feasibility of induction and consolidation with ATO followed by autologous HSCT in relapsed APL demonstrated a 5-year EFS of 65% and a 5-year OS of 77% [Yanada 2013]. Subsequent data suggest an improved 5-year DFS and OS in autologous HSCT when compared with allogenic HSCT (DFS 63% in autologous HSCT and 50% in allogenic HSCT [P = 0.10]; OS 75% in autologous HSCT versus 54% in allogeneic [P = 0.002]) [Holter Chakrabarty 2014].
In a retrospective study of patients who received ATO-based therapy before autologous HSCT, a delay in neutrophil recovery was observed, although the clinical significance is uncertain [Mannis 2014]. Owing to the increasing use of ATO in front-line therapy for APL, larger prospective studies are necessary to validate findings and to understand the mechanism of delayed neutrophil recovery [Mannis 2014].
Managing Special Situations
Follow the comprehensive recommendations for the management of situations requiring special consideration, including treating older and younger patients, patients with severe comorbidities, pregnant women and patients with therapy-related APL, in Table 5 (management of special situations).
| Current Recommendation |
|---|
| Older Patients |
| Manage elderly patients in good clinical condition with a treatment approach similar to that used in younger patients slightly attenuated in dose intensity |
| Patients with severe comorbidities |
| Consider older and younger patients with severe comorbidities who are unfit for chemotherapy (especially anthracyclines) as candidates to receive ATO-based treatment schedules |
| Children |
| Give ATRA in children and adolescents |
| Pregnant women |
| Management of APL in pregnancy requires the involvement of the patient, hematologist, obstetrician, and neonatologist |
| Avoid retinoids, which are highly teratogenic, in the first trimester unless the patient decides to have a termination of pregnancy |
| ATRA can be used in the second and third trimesters of pregnancy |
| Arsenic derivatives are highly embryotoxic and are contraindicated at any stage of pregnancy |
| In patients presenting in the first trimester and not wishing to have a termination of pregnancy, offer induction therapy with daunorubicin alone |
| Although chemotherapy appears reasonably safe in the second and third trimesters of pregnancy, it is associated with an increased risk of abortions and premature delivery |
| For patients receiving ATRA with or without chemotherapy during pregnancy, institute stringent fetal monitoring, with particular emphasis on cardiac function |
| For deliveries before 36 weeks gestation, give antenatal corticosteroids before preterm delivery to reduce the risk of morbidity and mortality associated with respiratory distress syndrome |
| After successful delivery, breastfeeding is contraindicated if chemotherapy or ATO is needed |
| Advise female patients against conceiving while exposed to ATRA or ATO for consolidation and maintenance therapy |
| Patients with therapy-related APL |
| Treat like patients with de novo APL, but modifications may be necessary taking into account cardiac toxicity and prior anthracycline exposure |
| Abbreviations: ATO, arsenic trioxide; ATRA, all-trans retinoic acid.
|
Managing Treatment-related Complications
The most common ATRA and ATO treatment-related complications for APL include
- Differentiation syndrome (DS)
- Pseudotumor cerebri (PTC)
- QTc prolongation and hepatic toxicity
- Hyperleucocytosis
- Hepatic toxicity.
The main recommendations for management of these complications associated with use of ATRA and ATO in APL are summarized in Table 6.
| Complication | Related Drug | 1Current European APL Recommendation |
|---|---|---|
| Differentiation syndrome | ATRA and/or ATO | Always institute i.v. dexamethasone 10 mg BID until complete resolution of signs and symptoms, on clinical suspicion of differentiation syndrome |
| Temporary discontinuation of differentiation therapy (ATRA or ATO) is indicated only in case of severe APL differentiation syndrome | ||
| Pseudotumor cerebri | ATRA | Temporary discontinuation of ATRA |
| Opiate analgesics to counteract headache | ||
| Steroids and diuretics (acetazolamide or osmotic diuretics) | ||
| QTc prolongation | ATO | In case of QTc prolongation (calculated with formulas other than Bazett) above 500 ms, withhold ATO until normalization of QTc interval and monitor the patient daily |
| ECG until resolution of the prolongation | ||
| Monitor electrolytes and replace to maintain potassium >2 mEq/l and magnesium >1.8 mg/dl | ||
| Possibly discontinue other medications prolonging QTc interval | ||
| Hyperluekocytosis | ATRA and/or ATO | A cytoreductive agent in case of WBC increase >10 x 109/L |
| Use gemtuzumab or anthracyclines (idarubicin and daunorubicin) to control leukocyte count | ||
| Consider using GO, anthracyclines or hydroxyurea to control WBC increase during induction therapy | ||
| Hepatic toxicity | ATRA and/or ATO | Monitor liver enzymes (AST, ALT, bilirubin and alkaline phosphatase) during ATO therapy. Temporarily discontinue ATO and/or ATRA in the event of raised liver enzymes (>grade 2 CTCAE), until normalization of hepatic function tests |
| Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATO, arsenic trioxide; ATRA, all-trans retinoic acid; CTCAE, Common Terminology Criteria for Adverse Events; GO gemtuzumab ozogamicin. | ||
Background to the Management of Treatment-related Complications
Differentiation syndrome (DS)
DS, previously referred to as retinoic acid syndrome) is a relatively common and potentially life-threatening complication that can occur during the first days or weeks after the start of ATRA and/or ATO. Clinical signs and symptoms include dyspnea, interstitial pulmonary infiltrates, unexplained fever, weight gain >5 kg, pleuro-pericardial effusion, hypotension, acute renal failure and peripheral edema. No single sign or symptom is diagnostic for DS as each may be associated with other conditions such as infection, septic shock, or hemorrhage [Frankel 1992].
The PETHEMA group revised the DS grading and classified patients into those with severe DS (>3 signs or symptoms) or moderate DS (2-3 sign or symptoms) [Montesinos 2009]. The incidence of DS was described by the same PETHEMA investigators to be higher during the first week of treatment, with a second lower peak in the third week of induction therapy.
Most ATRA-chemotherapy and ATRA-ATO regimens adopted nowadays include steroid prophylaxis. Preventive treatment is particularly important in high-risk patients (WBC>10×109/L) given their increased risk of DS. For the treatment of overt or suspected DS, expert panels recommend the prompt use of intravenous dexamethasone 10 mg BID until resolution of signs and symptoms or for a minimum of 3 days [Sanz 2014]. Discontinue ATRA and/or ATO treatment only in case of severe DS.
Pseudotumor cerebri (PTC)
PTC is a rare but peculiar complication of ATRA therapy, with a reported incidence of 3% in the largest international trials (Sanz 2009]. PTC is mostly observed in children and adolescents, and is characterized by headache as the main presenting symptom with clinical signs of papilledema, provided the exclusion by cerebral imaging of intracranial space-occupying lesions and alteration of the CSF.
QTc prolongation and hepatic toxicity
QTc prolongation is a common and well-documented side effect of ATO that is not observed with ATRA treatment. QT prolongation can lead to torsade de pointes-type ventricular arrhythmia, which can be potentially fatal. The GIMEMA-SAL-AMLSG APL0406 trial reported prolonged QTc interval in 15 patients in the ATRA-ATO group (16%) [Lo-Coco 2013]. Clinically significant arrhythmias are very rare and none have been reported in the most recent trials employing ATO as first-line therapy.
In patients with a prolonged QTc interval above 500 msec, international guidelines recommend to maintain potassium and magnesium concentrations above 4.0 mEq/L and 1.8 mg/dL; ATO should be withheld; electrolytes repleted; and other drugs that may cause prolonged QTc interval potentially discontinued until normalization of the QTc [Seftel 2014].
US investigators assessed QT intervals in 113 non-APL patients treated with ATO using 4 different correction formulae of the QT interval [Roboz 2014]. With the commonly used Bazett rate correction formula, 90% of patients had QTc >470 ms, including 65% above 500 ms. By using other rate correction formulae (i.e. Framinghan, Fredericia), only 24% to 32% of patients had rate-corrected QT intervals above 500 ms. It is therefore conceivable that 500 ms QTc calculated with formulae other than Bazett should be an acceptable threshold to withhold ATO treatment [Roboz 2014].
Hepatic toxicity has frequently been reported in studies employing ATO with or without ATRA, especially in terms of increase in liver enzymes (mostly AST and ALT, less frequently alkaline phosphatase and bilirubin). This complication may occur in up to 60% of cases [Lo-Coco 2013], however it is generally reversible and successfully managed with decreased or temporary discontinuation of ATO and/or ATRA. No cases of hepatic failure have been reported in recent trials [Lo-Coco 2013; Burnett 2015].
Hyperleukocytosis
The development of hyperleukocytosis is a well-known and frequent side effect occurring in APL patients receiving ATO and/or ATRA. In study APL0406 including low- and intermediate-risk patients, leukocytosis defined as WBC >10×109/L was reported in 47% of patients in the ATRA-ATO combination group and was managed using hydroxyurea as per protocol recommendation [Lo-Coco 2013].
In the NCRI Study AML17, patients with a peripheral WBC count of >10×109/L at baseline (high risk) had provision to receive GO 3 mg/m2 on Day 1 of treatment and on Day 4 if the white count had not fallen below 10×109/L. In addition, a fraction of low-risk patients developing hyperleukocytosis received a single dose of GO upon increase in WBC count to 10×109/L [Burnett 2015].