Case study 13.1

A 24-year-old Chinese female was diagnosed with FAB-M2 acute myelogenous leukemia (AML). Her initial diagnostic work-up was remarkable for the presence of a diploid karyotype, with molecular studies notable for FLT3 internal tandem duplication mutation (FLT3–ITD) and wild-type NPM1. She achieved complete morphologic and molecular remission following standard induction with the “7 + 3” regimen. She has an identical twin and a second sibling who is a half (5/10) HLA match. An unrelated donor search yielded multiple 8/10 HLA matches. She recently completed her first consolidation with high-dose cytarabine and remains in complete morphologic remission with persistent polymerase chain reaction (PCR) positivity for FLT3–ITD.

1. What would be the best approach at this time?

Maintenance with sorafenib 300 mg twice daily
Four cycles of high-dose cytarabine (3 g/m²)
Syngeneic hematopoietic stem cell transplantation (HSCT)
8/10 matched unrelated donor HSCT
Haploidentical HSCT

Available data suggest that clinical outcomes for FLT3–ITD-positive patients are significantly improved when allogeneic transplantation consolidation is used compared to nontransplant alternatives.

Cytogenetics at diagnosis is the most important prognostic factor in AML, and the benefit of aggressive consolidation strategies such as allogeneic stem cell transplantation in first remission (CR1) in high-risk cytogenetic patients is well established. In approximately 50% of AML patients with normal karyotype, the presence of FLT3–ITD mutation is associated with increased rates of relapse and inferior survival. This finding remains the most powerful molecular indicator of adverse outcomes. Available data suggest that allogeneic transplant in early CR1 may improve the long-term outcomes for patients with FLT3–ITD mutation AML.

Although there have been no prospective trials demonstrating that allogeneic stem cell transplantation improves overall survival in FLT3–ITD mutated patients, multiple retrospective series have shown that survival was significantly improved when allogeneic transplantation was compared to nontransplant alternatives such as high-dose cytarabine and targeted therapy. This series included patients who underwent allogeneic transplantation from various donors, including haploidentical matches. DeZern and colleagues (2011) reported the outcomes of 133 patients with AML, 31 of them with the FLT3–ITD mutation. Overall survival for this group was similar compared with that of 102 patients with wild-type FLT3–ITD (WT-FLT3–ITD) treated during the same 4-year time period. The authors suggested that the similar outcomes between the two groups was related to an aggressive transplant strategy, including the use of haploidentical donors for FLT3–ITD mutated patients in CR1, and they advocated for the use of allogeneic HSCT over chemotherapy or targeted therapy as a consolidative strategy in this group of patients.

Schlenk et al. (2008) correlated the NPM1, FLT3, CEBPA, MLL, and NRAS mutational status with the clinical outcomes of 872 patients with cytogenetically normal AML treated in four different clinical trials. Thirty-one percent of screened patients (164/531) had FLT3–ITD mutations. These patients were then “genetically randomized” to undergo allogeneic HSCT if a matched related donor was available, versus consolidation with high-dose cytarabine (HiDAC) or autologous transplantation for those patients without a donor. Of the 663 patients who received postinduction therapy, 150 underwent HSCT from an HLA-matched related donor. Among complete responders, there was a significantly longer relapse-free survival (P = 0.009) in those who underwent transplantation. This finding was especially true for patients with FLT3–ITD mutation or “triple negative” (wild-type (WT) NPM1, CEBPA without FLT3–ITD), but not for patients with mutated NMP1 without FLT3–ITD mutation.

Most recently, Huang and colleagues (2012) reported the results of a prospective, patient self-selected trial comparing haploidentical related donor stem cell transplantation (n = 58) with chemotherapy (n = 74) as postremission consolidation for patients with intermediate- or high-risk AML in CR1. The incidence of relapse was significantly lower in the haploidentical transplant group compared to the chemotherapy group (12.0% vs. 57.8%; P < .0001). This translated into a significantly superior survival benefit for patients who underwent transplantation compared to those who received chemotherapy alone (4-year disease free survival (DFS): 73.1% vs. 44.2%; P < .0001; 4-year overall survival (OS): 77.5% vs. 54.7%; P = .001). Postremission treatment (matched-related donor-HSCT vs. chemotherapy) and high white blood cell (WBC) count at diagnosis were identified as independent risk factors affecting relapse, DFS, and OS on multivariate analysis.

Data to support haploidentical stem cell transplantation for FLT3-ITD mutated patients are insufficient at this time. However, in this case the high risk of disease relapse, the likely benefit from graft-versus-leukemia (GVL) effect, and the prompt availability of a suitable donor improved outcomes with haploidentical transplantation the preferred option, especially when compared to an 8/10 mismatched donor or syngeneic HSCT. An 8/10 mismatched unrelated donor transplant is associated with a high incidence of both graft-versus-host disease (GVHD) and transplant-related mortality (TRM) and is no longer performed at most centers.

Case study 13.2

A 27-year-old man with relapsed AML following a matched-related donor stem cell transplant was referred to your clinic for further treatment recommendations. Three years ago, he was diagnosed with AML-M4 with diploid cytogenetics, FLT3-ITD mutation negative, and NPM1 mutation positive. He achieved complete remission (CR) after standard induction therapy with the “7 + 3” regimen. After relapsing 9 months later, the patient underwent re-induction therapy, again achieved CR, and received a matched sibling donor transplant. The posttransplant course was uncomplicated, and his immunosuppressive therapy was tapered without evidence of GVHD. Unfortunately, he relapsed on day +380 with findings of 90% blasts in the bone marrow. He achieved a complete morphologic remission following salvage with a clofarabine-based regimen. On his most recent evaluation, a mutation in exon 12 of the NPM1 gene was still detectable by PCR.

1. What is the best treatment strategy at this time?

Supportive care and close clinical observation
Donor lymphocyte infusion from his prior sibling donor
A second matched related donor HSCT using a different conditioning regimen
A cord blood transplant
Azacitidine maintenance indefinitely

Younger, fit AML patients with posttransplant relapse should be considered for second allogeneic HSCT if relapse occurred more than 6 months after the first HSCT and the patient achieved CR after salvage chemotherapy.

There is no consensus on the optimal management of AML relapse following transplant, and outcomes for patients who relapse following allogeneic stem cell transplantation are dismal. In general, patients with remissions lasting more than 6 (and especially more than 12) months and those achieving CR are more likely to benefit from a second allogeneic transplant. A retrospective, multicenter study from International Bone Marrow Transplant Registry (IBMTR) analyzed the outcomes of 125 patients with relapsed AML following stem cell transplantation who went on to receive a second HLA-identical sibling transplant. Risk of subsequent relapse was lower in patients who relapsed more than 6 months following first transplant (relative risk (RR): 3.02; P = 0.0001) and in patients who achieved CR prior to second transplantation (RR for relapse for patients with persistent disease: 2.47; P = 0.0001). Overall survival was superior for patients with prolonged posttransplant remission and for those younger than 20 years of age. For patients who met these criteria, 5-year OS was 51% compared to 3% in those who did not.

Outcomes for donor lymphocyte infusion (DLI) recipients in the posttransplant relapse setting are poor, with brief remissions seen in about 15% of patients. The European Bone Marrow Transplantation Registry (EBMT) reported on the outcomes of 171 patients with relapsed AML following HSCT who went on to receive DLI as salvage therapy. The benefit of DLI was limited to patients with normal cytogenetics, those with low tumor burden at time of relapse, and those who achieved CR prior to DLI. In a young patient with chemosensitive relapse and goal to treat with curative intent, observation alone would not be an appropriate choice. Maintenance therapy with azacitidine might be a reasonable option in older patients, those without a donor, or in younger patients as a bridge to a second HSCT. Sorafenib therapy would not be curative, and in a patient with persistence molecular residual disease, a second transplant with a readily available donor would be a more suitable choice.

Case study 13.3

An active and otherwise healthy 70-year-old man was recently diagnosed with AML and referred to you following completion of induction chemotherapy. The patient originally presented after atypical cells were incidentally found on a preoperative work-up prior to an elective surgical procedure 2 months ago. A bone marrow biopsy demonstrated the presence of leukemic blasts occupying 70% of the marrow space; karyotype revealed deletion of chromosome 7 in 8/20 metaphases. Patient received induction therapy with cytarabine 200 mg/m² and daunorubicin 45 mg/m². He achieved a complete morphologic and cytogenetic remission 6 weeks after induction therapy. He is an only child and has three healthy adult sons; a full HLA-matched unrelated donor was identified within the donor registry. The patient and his family are inquiring about the best curative approach at this time.

1. What do you recommend?

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13: Hematopoietic Cell Transplantation in Acute Myeloid Leukemia

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